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Bone marrow transplantation in auto-immune disease
4 Bone marrow transplantation in auto-immune disease J O H N A. H A M I L T O N J A M E S C. B I G G S KERRY ATKINSON P E T E R M. B R O O K S
Auto-immune diseases such as systemic lupus erythematosus (SLE), scleroderma and rheumatoid arthritis (RA) cause significant morbidity and mortality (Pincus, 1988; Fessler and Boumpas, 1995) and, although modem aggressive treatments may suppress disease activity in many cases, few if any complete cures for these diseases are reported. Over the last decade a more aggressive approach to these conditions, with the use of multiple immunosuppressive drugs given at an early stage in the disease, have been shown to be beneficial in diseases such as lupus renal disease (Klippel, 1990), but whether this approach significantly improves long-term outcome in rheumatoid arthritis is as yet unclear. The use of specific cytokine blockade has heralded a new direction in the management of rheumatoid arthritis and has recently been shown to be successful in the short term (Elliott et al, 1994). Whether this approach will sustain remission is yet to be proven. Our relative impotence in terms of management of these conditions demands a re-think of the aetiopathogenesis of these diseases and their treatment. SCIENTIFIC BASIS Dysregulation in autoreactive lymphocytes and bone marrow stem cells
Lesions in auto-immune diseases contain mature haemopoietic cells, such as lymphocytes and macrophages, which obviously play key roles in the pathogenesis. For example, they can be involved in the recognition and destruction of target tissue, and can be a source of many potential mediators of local immune and inflammatory reactions, such as cytokines, enzymes, free radicals etc. Whether auto-antigens are primarily responsible as triggers for the initial phase of disease or become significant in later stages due to, for example, cross-reactivity with an aetiological agent or to expression as a result of tissue damage, is a matter that is still widely debated. Bailli~re's Clinical Rheumatology673 Vol. 9, No. 4, November 1995 ISBN 0--7020-2076-1
Copyright 9 1995, by Bailli6re Tindall All fights of reproduction in any form reserved
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In adults, haemopoietic cells derive from precursor cells in the bone marrow by proliferation and differentiation. Auto-immune diseases are usually considered as arising from some type of immune dysfunction. There are cases of animal models where disease can be transferred by mature lymphocytes. Examples of such disease transfer into recipient animals include those where arthritis and experimental allergic encephalomyelitis (EAE) can be passed with spleen cells or cloned T cells from symptomatic animals to normal syngeneic ones (Pearson and Wood, 1964; Matsumoto and Fujiwara, 1988). Since the thymus has a significant role in the positive and negative selection of T cells and is apparently involved in the deletion of autoreactive clones, it has been considered that the aetiopathogenesis of both systemic and organ-specific auto-immune diseases could be attributed to defects in the thymus. However, there are many cases with animal studies which suggest that the auto-immune diseases originate from defects that reside in haemopoietic stem cells since some of the abnormalities of mature lymphocytes are transferrable with bone marrow cells (Morton and Siegel, 1974; Akizuki et al, 1978; Ikehara et al, 1990). In a number of murine models of auto-immune disease, such as lupus and insulin-dependent diabetes, there is one common feature of the mouse strains which develop disease--their pluripotent haemopoietic stem cells carry the information for the auto-immune phenotype which is ultimately expressed by more mature cells (Ikehara et al, 1990; Schwieterman et al, 1992). In other words, the auto-immune tendencies appear to be encoded in the cellular genome and are not directly dependent on the milieu of the surrounding tissue in which the stem cells expand and differentiate. It is also possible that the enhanced stem cell hyperplasia evident in some of the models might act to amplify and worsen the ongoing pre-existing auto-immune phenomena by supplying increased numbers of lymphocytes and monocytes, as well as their products (Schwieterman et al, 1992; Vieten et al, 1992). Granulocyte-macrophage colony-stimulating factor (GMCSF) has been shown to activate monocytes to express major histocompatability complex (MHC) antigens and adhesion molecules, and promote pro-inflammatory cytokine production (Gasson, 1991). Field and Clinton (1993) have recently demonstrated that significantly more monocytes from patients with rheumatoid arthritis express GM-CSF receptor than do those from healthy volunteers or patients with osteoporosis. Since GM-CSF is produced by synovial cells in RA, the continuing inflammatory response could be enhanced by activation of the entering monocytes. Bone and rheumatoid arthritis
In rheumatoid arthritis (RA), it is widely assumed that the development of the synovial pannus, as a vascular granulation tissue, is the sole primary event by which cartilage is first destroyed. However, in synovectomy studies performed a number of years ago on early RA lesions, proliferative changes in the periosteum and perichondrium were observed in the absence of a 'pannus' (Mills, 1970); it was suggested that the pannus was an endresult rather than a cause of the cartilage breakdown. In early RA cases
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again, even when there was no macroscopic evidence of cartilage damage, a marked cellular reaction in the periosteum deep to the synovial layer was noted (Muirden, 1975). Osteoclastic and osteoblastic reactions were seen on the marrow surface of trabeculae. More recently there have been other reports of abnormalities in bone marrow cells of RA patients, such as abnormal myeloid cells (Ochi et al, 1988), enhanced monocyte DNA synthetic activity (Dreher et al, 1986), higher than normal numbers of mononuclear cells positive for HLA DR and CD14 (Seitz et al, 1992), abnormally high myeloid growth factor activity and myeloid precursor numbers in bone marrow next to affected joints (Owaki et al, 1989; Kotake et al, 1992), increased numbers of mononuclear cells in the iliac bone marrow (Tomita et al, 1994) and differences in T-cell subsets suggestive of immunological activation (Doita et al, 1990). It has therefore been considered that severe RA is associated with an aberrant proliferation of bone marrow myeloid cells adjacent to affected joints (Ochi et al, 1988; Owaki et al, 1991); in addition, it has been claimed that changes in the iliac bone marrow point to an important role of systemic bone marrow in the progression of RA (Tomita et al, 1994). The bone marrow abnormalities listed above presumably reflect enhanced haemopoietic activity there as part of an immune or chronic inflammatory reaction associated with the development of RA. Alternatively, there could be an inherent dysregulated haemopoiesis of unknown aetiology analogous to the murine auto-immune models described above. There are reports that about 30% of patients with RA have peripheral blood monocytosis (Buchan et al, 1985) and that the mononuclear cell population contains 50% monocytes, compared with 23% monocytes in healthy controls (Seitz et al, 1982). Also, thrombocytosis is common in acute and severe rheumatoid disease. Slow-acting anti-arthritic drugs and bone marrow
Drugs such as gold compounds, o-penicillamine, antimalarials and methotrexate are given to slow down or halt RA progression. Several mechanisms to account for the therapeutic benefit of these drugs have been suggested, including immunological and anti-inflammatory effects. During treatment with these disease-modifying drugs, the white blood cell count is monitored routinely. A trend towards a fall in white cell or platelet numbers is an indication to stop treatment or lower the dose and one of the more serious effects of these drugs is leukopenia. A reduction in myeloid progenitor cell numbers in the bone marrow, coinciding with leukopenia, has been reported for a RA patient treated with gold thiomalate (Howell et al, 1975). It has been proposed that the penicillamine-induced thrombocytopenia in RA patients is due to bone marrow suppression (Thomas et al, 1984) and there is data to show that human myeloid bone marrow progenitor cells in vitro are extremely sensitive to the growth inhibitory effects of diseasemodifying drugs (Hamilton and Williams, 1985, 1987). On the basis of observations such as these, it has been proposed that disease-modifying antirheumatic drugs act by inhibiting myelopoiesis thus reducing slowly
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the numbers of inflammatory cells present in lesions (Hamilton and Williams, 1985, 1987; Hamilton, 1993). In other words, their efficacy may in fact be due to their myelotoxic or bone marrow suppressive activities. Bone marrow transplantation
The above discussion has presented some evidence for the involvement of autoreactive lymphocytes in auto-immune disease, for a defect in the bone marrow stem cells in hereditary experimental auto-immune disease, and for the involvement of altered bone marrow in RA patients. Unless the pathogenic population of autoreactive lymphocytes is depleted in auto-immune disease, established disease will be self-sustaining and intervention with agents such as the new cytokines or monoclonal antibodies may have to be given for life. Scientifically speaking, such a depletion is feasible with allo-bone marrow transplantation (BMT); the results from such approaches will be presented below. Alternatively, it has been proposed that if mature autoreactive lymphocytes could be eliminated and the immune system allowed to redevelop from autologous precursors, the chance of redeveloping a particular auto-immune disease should approach the rate of incidence in unaffected monozygotic twins (Carson, 1992). This idea is more likely to be relevant if any aetiological agent(s) relevant to an auto-immune disease were present early in life and therefore would not influence the development of the reconstituted immune system. Given the recent knowledge regarding lymphocyte differentiation and availability of cytokines controlling such differentiation, this type of therapeutic approach is now feasible. Some experimental support for the possibility of successful clinical autologous BMT is the perhaps surprising result that adjuvant arthritis and EAE could be resolved by immune ablation followed by autologous stem cell transplantation (van Bekknm, 1993). As mentioned, in a disease such as RA, there may also be defects in cells of the myeloid lineages, such as the macrophages, which could be inappropriately 'activated' to produce inflammatory mediators. In fact, the type of cell in the rheumatoid synovium which correlates best with the degree of joint erosion is the macrophage. A similar rationale for the value of their depletion, as enunciated above for the depletion of autoreactive lymphocytes, can be applied. Perhaps the ablation portion of any BMT therapy used successfully in RA disease (Lowenthal et al, 1993) is in fact already occurring in a mild way, as pointed out above, during treatment with disease-modifying drugs (Hamilton, 1993). ANIMAL MODELS Both allogeneic and autologous bone marrow transplantation has been shown to modify and, in some instances, reverse a variety of animal models of auto-immune disease (Table 1). van Bekkum et al (1989) reported the regression of adjuvant induced arthritis in rats and showed that tmns-
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plantation of syngeneic bone marrow was as effective as allogeneic bone marrow from rat strains not susceptible to induction of adjuvant arthritis. The treatment was most effective when applied shortly after the clinical manifestation of the arthritis occurred, i.e. within 4-7 weeks after administration of mycobacterium tuberculosis. Nakagawa et al (1993) demonstrated that auto-immune polyarthritis could be prevented in male New Zealand black mice prone to developing this disease after transplantation with bone marrow cells (which will recruit stromal cells) plus bone from normal donors. They had previously shown that bone marrow transplantation alone was not successful in treating these diseases but that bone marrow cells plus bone transplantation rendered the joint bones radiologically and histopathologically normal and the mice demonstrated decreased production of anti-single-stranded DNA antibodies and rheumatoid factors at 8-12 months of age. Table 1. Animal models demonstrating BMT effect on disease.
Model
Result
Reference
Adjuvant arthritis (rats) Auto-immune polyarthritis (mice) Auto-immune nephritis and coronary vascular disease (mice) SLE (mice) Diabetes (nude mice) Diabetes (nude mice) Auto-immune encephalomyelitis (mice) Anto-immune encephalomyelitis (mice)
Regression of disease Prevention Prevention
van Bekkum et al (1989) Nakagawa et al (1993) Mizutani et al (1993)
Prevention Prevention Prevention Prevention Reversal
Marmot (1993) lkehara et al (1985) Georgiou et al (1993) lkehara et al (1985) van Gelder et al (1993)
Mizutani et al (1993) studied auto-immune mice (W/B) who developed systemic auto-immunity involving the production of auto-antibodies, thrombocytopenia, lupus nephritis and coronary vascular disease with myocardial infarction. Transplantation of T-cell depleted marrow gave a 90% protection in the recipients from the development of lupus and no mice developed coronary vascular disease. A number of other animal studies have shown that auto-immune disease including spontaneous lupus in mice can be prevented by bone marrow transplantation (Marmot, 1993). Diabetes, which occurs spontaneously in the nude mouse model and which is due to an auto-immune T-cell-mediated insulinitis, can be both transferred from the nude mouse to normal recipients and prevented by bone marrow transplantation of the nude mice (Ikehara et al, 1985; Georgiou et al, 1993). Another auto-immune disease---experimental allergic encephalomyelitis (EAE)---can also be shown to be prevented and the clinical manifestations reversed by allogeneic, syngeneic and autologous haemopoietic stem cells (Karussis et al, 1993; van Gelder et al, 1993). Levite et al recently showed that experimental SLE can be induced in mice by immunization with either a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id) or with a mouse monoclonal antiidiotypic antibody specific for the 16/6 Id. Susceptibility to the induction of
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the experimental SLE is genetically determined and not linked to the MHC. The susceptibility of bone marrow chimeras of different donor host combinations to the induction of SLE has been studied and high levels of anti 16/6 Id and anti-ss-DNA antibodies are induced in some of these animals but not in others. Low levels of the anti 16/6 Id and anti-ss-DNA antibodies are produced by the C57 BL/6--->BALB/c chimeras immunized with 16/6 Id. Following allogeneic BMT such chimeras will produce high levels of antibodies to a T-cell-dependent antigen, suggesting that the production of SLE-related autoantibodies is controlled by donor type BM derived cells and not by host type cells in the thymic stroma. These animal experiments show clearly that allogeneic, syngeneic and autologous transplantation can be used to both transfer these diseases and prevent, or at least modify, their immunopathology. These data suggest that the pluripotential bone marrow cells may have an important role to play in these diseases and provide the basis for experimentation of these interventions in humans. CLINICAL BLOOD AND BONE M A R R O W TRANSPLANTATION It is now more than 35 years since E. D. Thomas and co-workers reported that large quantities of bone marrow could be safely infused into humans and that transient engraftment of haemopoietic cells was possible. Since then, clinical bone marrow transplantation has become widely utilized and is capable of curing a number of acquired and congenital disorders of the haemopoietic, immune and metabolic systems (Atldnson, 1994; Forman et al, 1994). It is now beginning to be applied to solid tumours such as breast and testicular cancer. Haemopoietic stem cells are likely also to be a prime vehicle for gene therapy. The source of haemopoietic stem cells for transplantation may be either an HLA-identical family member or unrelated volunteer (allogeneic transplantation), an identical twin (syngeneic transplantation) or from the recipient himself or herself (autologous transplantation) (Table 2). In the latter situation the marrow should not overtly be involved by disease at the time of harvest. This may have implications for the treatment of autoimmune disease. Table 2. Types of bone marrow transplants. Type
Source of haemopoietic stem cells
Autologous Syngeneic Allogeneic HLA-identical family member
Patient Identical twin
HLA-non-identical family member HLA-identical unrelated donor
Usually HLA-identical sibling (occasionally parent, child, other) Family member matched for five of the six HLA-A, -B and -DR antigens Unrelated volunteer
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Blood stem cells are widely utilized instead of marrow stem cells as a source of haemopoietic stem cells in autologous transplantation and increasingly in allogeneic transplantation. This is because blood cells can be extracted from the circulation in huge numbers using a cell separator machine after their mobilization from the marrow cavity, either by chemotherapy or haemopoietic growth factors or both. They can then be cryopreserved while the patient receives the high-dose chemotherapy or chemoradiotherapy treatment aimed at ablating the underlying disease. Once this is completed the blood stem cells can be thawed and re-infused into the recipient to allow recovery from the marrow ablative treatment. The increased number of haemopoietic stem cells present in a blood stem cell transplant compared to a marrow transplant results in accelerated recovery of both neutrophil and platelet counts post transplant, rendering the procedure safer with less risk of infection and haemorrhage respectively (Table 3) (Sheridan et al, 1992).
Table 3. Source of haemopoietic stem cells. Source
Advantages
Disadvantages
Marrow
No mobilization required
General or spinal anaesthetic; short inpatient admission Slower recovery of blood count in recipient
Blood
No anaesthetic; outpatient procedure Faster recovery of blood count in recipient May have less tumour cell contamination than bone marrow Can be obtained from patient with marrow damage (e.g. previous pelvic radiotherapy)
TECHNIQUE The technique of haemopoietic stem cell transplantation (blood or marrow) is relatively simple. It involves first the identification of a suitable source of haemopoietic stem cells. If this is from the recipient (autologous transplant), these are usually harvested either from the blood or from the marrow and cryopreserved in liquid nitrogen at -179~ They can be kept at this temperature indefinitely. If the donor is an HLA-compatible normal person (relative or unrelated volunteer donor), the marrow or blood haemopoietic stem cells are normally harvested and infused fresh on the day of transplant. The principle behind marrow transplantation is that very-high-dose chemotherapy or chemoradiotherapy (including total body irradiation) is given to ablate the underlying disease (Table 4). Diseases primarily treated by allogeneic transplantation or by autologous transplantation are shown in Table 5. For allogeneic transplantation it is also necessary to eradicate the recipient's immune system so that he or she will accept the incoming donor graft.
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J. A. HAMILTON ET AL Table 4. Technique of haemopoietic stem cell transplantation. 1. High-dose chemotherapy or chemoradiotherapy 2. Intravenous infusion of haemopoiefic stem cells
Table 5. Diseases treatable by haemopoietic stem cell transplantation. AML ALL CML CLL
Myelodysplasia Myeloma
Myelofibrosis Hodgkin's disease
Non-Hodgkin's disease Breast cancer Testicular cancer Ovarian cancer
Childhood solid tumours Severe aplastic anaemia Fanconi's anaemia Thalassemia major
Severe combined and other congenital immune disorders
Allogeneic transplant
Autologous transplant
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes
No No No No Yes Yes Yes Yes
Experimental Experimental No Yes No Yes Yes Yes Yes
Experimental Yes No No No No
AML = acute myeloid leukaemia; ALL = acute lymphoblastic leukaemia; CML = chronic myeloid leukaemia; CLL = chronic lymphatic leukaemia.
As a consequence of this high-dose chemotherapy/chemoradiotherapy the recipient's marrow is ablated and such high dosage cannot be used unless a source of haemopoietic stem cells is available afterwards to allow marrow repopulation and blood count recovery. M A R R O W HARVEST This is normally performed under general anaesthetic or under spinal anaesthesia. Marrow is aspirated by needle punctures into the posterior superior iliac crests; 5 ml of marrow is aspirated each time until approximately 3 x 108 nucleated marrow cells/kg recipient weight have been obtained. This figure allows for rapid allogeneic engraftment. ABO incompatibility between donor and recipient is not a barrier to allogeneic transplantation, but if a major ABO difference exists between the two, the recipient will normally undergo plasmapheresis to remove circulating isoagglutinins that would otherwise haemolyse the red cells in the incoming donor marrow. Additionally, the marrow itself is depleted of red cells prior to its infusion into the recipient.
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BLOOD STEM C E L L HARVEST If the source of stem cells is the blood rather than the marrow, blood stem cells are removed in the mononuclear cell component by a cell-separator machine. This procedure is carried out as an outpatient usually on several consecutive days and involves the blood stem cell donor having an intravenous cannula in each ann. The blood from one arm is taken to the machine which centrifuges the blood, separates the red cells from white cells and scoops the mononuclear cells into a bag. They are then cryopreserved. Red cells and plasma are returned to the recipient through the cannula in the opposite arm. Only minimal numbers of stem cells circulate in the normal basal state. Therefore, for blood stem cell harvest, marrow cells have to be mobilized into the blood stream. This is done either by use of a haemopoietic growth factor given to the blood stem cell donor for 4-7 days prior to blood stem cell harvest--usually granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytotoxic chemotherapy is an additional means of mobilizing marrow cells into the circulation and the highest numbers of blood stem cells are obtained using a combination of cytotoxic chemotherapy and a haemopoietic growth factor. Cytotoxic chemotherapy cannot of course be given to normal tissue compatible marrow donors, and in such circumstances blood stem cells are mobilized by haemopoietic growth factor administration. COMPLICATIONS OF A L L O G E N E I C M A R R O W OR BLOOD STEM CELL TRANSPLANTATION (Table 6)
Early post-transplant In the first 2-3 weeks after either allogeneic or autologous stem cell transplantation, the recipient's blood count is ablated by the nigh-dose chemotherapy/chemoradiotherapy, and he or she remains neutropcnic and thrombocytopenic for 10-20 days. Most recipients have an episode of febrile neutropenia which in the majority resolves satisfactorily with the early use of intravenous antibacterial antibiotics (Hughes et al, 1990), Table 6. Complications of haemopoietic stem cell transplantation.
Type of transplant
Early
Late
Allogeneic and autologous
Pancytopenia/infection Gastrointestinal Mucosal damage Haemorrhagic cystitis Hepatic veno-oeelusive disease Interstitial pneumonitis Alopecia
Infertility
Allogeneic
Acute graft-versus-host disease
Secondary malignancy Cataracts Growth stunting (children) Pubertal delay (children) Secondary malignancy Chronic graft-versus-host disease
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Also in the first 2-3 weeks post-transplant, the oropharyngeal and gastrointestinal mucosae are damaged by the high-dose chemotherapy/ chemoradiotherapy, producing ulceration and discomfort. Anorexia is universal, with some degree of discomfort, nausea, vomiting and diarrhoea. This situation is normally manageable with the use of opiate analgesia and intravenous total parenteral nutrition.
Unusual complications due to the high-dose chemotherapy/ chemoradiotherapy Rare complications that usually occur within the first few weeks post-transplant include haemorrhagic cystitis due to the effect of either high-dose cyclophosphamide, busulphan, etoposide or ifosfamide on the urothelium. The risk of this can be minimized by high-dose intravenous hydration during administration of the cytotoxic chemotherapy. Another complication of the high-dose chemotherapy is hepatic veno-occlusive disease due to intimal injury of the small hepatic venules. This can be minimized with the use of intravenous heparin during the period of chemotherapy administration and the first 3 weeks post-transplant, which reduces the risk of secondary coagulation on the damaged intima. Another rare complication of the high-dose cytotoxic chemotherapy is chemical pneumonitis, usually manifesting as interstitial pneumonitis. This may have to be diagnosed by lung biopsy to distinguish it from cytomegalovirus or Pneumocystis carinii pneumonia. Chemical pneumonitis often responds to prednisone therapy (Meyers et al 1982; McDonald et al, 1984; Thomas et al, 1987).
Late post-transplant A rare late complication of high-dose chemoradiotherapy and stem cell transplantation is secondary malignancy. This occurs more commonly after autologous than allogeneic transplantation. The commonest type of malignancy is myelodysplasia/acute myeloid lenkaemia which may occur in up to 10% of recipients of autologous transplants by 10 years post transplant (Stone, 1994). One complication of allogeneic transplantation that does not occur with autologous transplantation is graft-versus-host disease. This is mediated by mature donor T cells present in the donor inoculum which recognize histocompatibility antigen disparities present in the recipient and absent in the donor. It is usually preventable by a combination of cyclosporin and methotrexate immune suppression. This usually needs to be given for 6-12 months after allogeneic transplantation. Prothymocytes that are generated from the donor haemopoietic stem cells appear to be tolerized by transit through the recipient thymus, and immune suppression can usually be ceased relatively early after an allogeneic marrow transplant (in contradistinction to allogeneic solid organ transplants).
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EFFICACY OF H A E M O P O I E T I C STEM CELL TRANSPLANTATION The cure rate of marrow transplantation depends on the underlying disease, the status of the disease at the time of transplant, the source of haemopoietic stem cells and the physical condition of the recipient at the time of transplant (Table 7). Representative outcomes in terms of treatment-related mortality, relapse rate and disease-free survival rate for a number of different diseases and types of transplants are shown in Table 8. The range of disease in which BMT is beneficial and the mortality and morbidity rate is changing each year. Table 7. Factors affecting outcome of transplant.
Disease for which transplant is being performed Performance status of the recipient Degree of donor-recipient histocompatibility (allogeneie) Status of disease at the time of transplant Age of recipient
Table 8. Disease-free survival after haemopoietic stem cell transplantation'.
Disease
Allo transplant
Auto transplant
AML in first complete remission AML beyond first complete remission CML in first chronic phase CML beyond first chronic phase Hodgkin's disease in first relapse High-risk breast cancer Severe aplastic anaemia Thalassaemia major
70% 20% 80% 20% Insufficient data Not done 75% 70-95%
45% 20% < 5% 0 55% 70% Not done Not done
"For abbreviations see footnote to Table 5.
HUMAN EXPERIMENTS Bone marrow transplantation has been used as a treatment for gold-induced thrombocytopenia in patients with rheumatoid arthritis (Adachi et al, 1987) and there are a number of cases in the literature where bone marrow transplantation done for other reasons (co-existing neoplastic disease or drug-induced aplasia) has produced a remission in patients with rheumatoid arthritis. The majority of these patients have been reported to have longterm remissions, although there are instances where the disease has returned some years later associated with a rise in the rheumatoid factor. Other auto-immune diseases such as psoriasis and ulcerative colitis have also been shown to go into sustained remission following bone marrow transplantation (Eedy et al, 1990; Liu Yin and Jowitt, 1992). Recently a case of auto-immune mixed cryoglobulinaemia with vasculitis and nephritis was successfully treated with myeloablating immunosuppressive treatment followed by autologous stem cell transplantation (Slavin, 1993).
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On the other hand, cold-agglutinin disease has been reported following aUogeneic bone marrow transplantation (Tamura et al, 1994) and there are a number of cases where insulin-dependent diabetes has been transferred from donors to recipients (Lampeter et al, 1993), Data from animal models suggest that syngeneic transplantation will significantly modify auto-immune disease, although this has not yet been attempted in humans. The lower mortality and morbidity of this form of transplantation makes it an attractive option in these non-fatal conditions. The critical question is whether the stem cells are already affected by the disease. One might argue that the genetic susceptibility to developing rheumatoid arthritis or SLE may well continue even if the disease is put into remission but it must be remembered that the genetic component is but one of a number of risk factors in these diseases. In developing a therapy that has the potential to cure these auto-immune diseases, it will be important to use them early in the disease before damage to vital organs has occurred. Identification of these patients who will have a bad outcome is now becoming a reality at least in diseases such as rheumatoid arthritis. Gough et al (1994) have recently demonstrated that the presence of conserved base sequences in the third hypervariable region of the DrB1 gene and the presence of rheumatoid factor provide a relative risk of eight for the development of erosions at 1 year. The presence of DW4 and DW14 was an even more powerful predictor of erosion formation. BMT will never be a treatment for all auto-immune diseases, but the potential for cure, coupled with our increasing ability to identify those patients with auto-immune disease who are at high risk of doing particularly badly, demand that we carefully evaluate the procedure and the outcome. BMT for auto-immune disease remains an experimental treatment, but its potential for cure of these conditions requires that it be carefully evaluated. International collaboration is required to develop guidelines for the selection of patients and for the procedure, especially the type of transplantation to be carded out and the immunosuppressive regimen to be given. No single unit is going to have sufficient patients to provide meaningful data so that international co-operation is vital to evaluate this potentially curative therapy rapidly.
Acknowledgements The support of the Clive and Vera Ramaciotti Foundation is acknowledged.
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Buchan GS, Palmer DG & Gibbins BL (1985) The response of human peripheral blood mononuclear phagocytes to rheumatoid arthritis. Journal of Leukocyte Biology 37: 221-230. Carson DA (1992) Genetic factors in the etiology and pathogenesis of antoimmunity. FASEB Journal 6: 2800-2805. Doita M, Maeda S, Kawai K et al (1990) Analysis of lymphocyte subsets of bone marrow in patients with rheumatoid arthritis by two colonr immunofluorescence and flow cytometry. Annals of the Rheumatic Diseases 49: 168-171. Dreher R, Robe-Oltmanns B, Fink K & Seidel H (1986) Pathogenese und therapie der rheumatisehen entzuodung, lmmunisation and lnfektion 3: 100-108. Eedy DJ, Burrows D, Ridges JM & Jones FJC (1990). Clearance of severe psoriasis after allogeneie bone marrow transplantation. British Medical Journal 300: 908-909. Elliot MJ, Maini RN, Feldmann M e t al (1994) Raodomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor ct (CA2) versus placebo in rheumatoid arthritis. Lancet 344:1105-1110. Fessler BJ & Boumpas DT (1995) Severe major organ involvement in systemic lupus erythematosus. Rheumatic Disease Clinics of North America 1: 81-98. Field M & Clinton L (1993) Expression of GM-CSF receptors in rheumatoid arthritis. Lancet 342: 1244. Forman SJ, Blume KG & Thomas ED (eds) (1994) Bone Marrow Transplantation. Boston: Blackwell Scientific Publications. Gasson JC (1991) Molecular physiology of granuloeyte macrophage colony stimulating factor. Blood 77:1131-1145. Georgiou HM, Slattery RM & Charlton B (1993) Bone marrow transplantation prevents auto-immune diabetes in non-obese diabetic mice. Transplantation Proceedings 25: 2896-2897. Gough A, Faint J, Salmon M e t al (1994) Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis & Rheumatism 37" 1166-1170. Hamilton JA (1993) Hypothesis. Rheumatoid arthritis: opposing actions of haemopoietie growth factors and slow-acting anti-rheumatic drugs. Lancet 342: 536-539. Hamilton JA & Williams N (1985) In vitro inhibition of myelopoiesis by gold salts and Dpenicillamine. Journal of Rheumatology 12: 892-896. Hamilton JA & Williams N (1987) Effects of anranofin and other anti-rheumatic drugs on human myelopoiesis in vitro. Journal of Rheumatology 14: 216-220. Howell A, Gumpel JM & Watts RWE (1975) Depression of bone marrow colony formation in goldinduced neutropeni& British Medical Journal i: 432--434. Hughes WT, Armstrong D & Bodey GP (1990) Guidelines for the use of antimicrobial agents in nentropenie patients with unexplained fever. Journal of Infectious Diseases 161: 381-396. Ikehara S, Ohtjuki H, Good RA et al (1985) Prevention of type I diabetes in non-obese diabetic mice by allogeneie bone marrow transplantation. Proceedings of the National Academy of Sciences of the USA 82: 7743-7747. Ikehara S, Kawamura M, Takao F et al (1990) Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. Proceedings of the National Academy of Sciences of the USA 87: 8341-8344. Ishida T, Inaba M, Hisha H e t al (1994) Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. Complete prevention of recurrence of autoimmune diseases in MRL/MP-Ipr/Ipr mice by transplantation of bone marrow plus bones (stromal ceils) from the same donor. Journal oflmmunalogy 152:3119-3127. Jacob D, Vincent MD & Marteu RW (1986) Prolonged remission of severe refractory rheumatoid arthritis following allogeneic bone marrow transplantation for drug induced aplastic anaemia. Bone Marrow Transplantation 1: 237-239. Karussis DM, Vourka-Karussis U, Lehmann D et al (1993) Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. Journal of Clinical Investigation 92: 765-772. Klippel JH (1990) Systemic lupus erythematosus. Treatment related complications superimposed on chronic disease. Journal of The American Medical Association 263: 1812-1815. Kotake S, Higaki M, Sato K et al (1992) Detection of myeloid precursors (granuloeyte/macwphage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints. Journal of Rheumatology 19: 1511-1516. Lampeter EF, Horuberg M, Quabeck K et al (1993) Transfer of insulin dependent diabetes between HLA--identical sibling by bone marrow transplantation. Lancet 341: 1243-1244.
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Levite M, Zinger H, Mozes E & Reisner Y (1993) Systemic lupus erythematosis-related auto antibody production in mice is determined by bone marrow derived cells. Bone Marrow Transplantation 12: 179-183. Liu Yin JA & Jowitt SN (1992) Resolution of immune mediated diseases following allogeneic bone marrow transplantation for leukaemia. Bone Transplantation 9: 31-33. Lowenthal RM, Cohen ML, Atkinson K & Biggs JC (1993) Apparent cure of rheamatoid arthritis by bone marrow transplantation. Journal of Rheumatology 20: 137-140. McDonald GB, Shamarm AP, Mathews DE et al (1984) Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence and predisposing factors. Hepatology4: 116--122. Marmot AM (1993) Immune ablation with stem cell rescue: a possible cure for systemic lupus erythematosus. Lupus 2:151-156. Marmot AM (1994) Immune ablation followed by allogeneic and autologns bone marrow transplantation: a new treatment for severe autoimmune disease. Stem Cells 12: 125-135. Matsumoto Y & Fujiwara M (1988) Adoptively transferred experimental allergic encephalomyelitis in chimeric rats: identification of transferred cells in the lesions of the central nervous system. Immunology 65: 23-29. Meyers JD, Floumoy N & Thomas ED (1982) Non-bacterial pneumonia after allogeneic marrow transplantation: review of 10 years experience. Reviews of Infectious Diseases 4:1119-1132. Mills K (1970) Pathology of the knee joint in rheumatoid arthritis. A contribution to the understanding of synovectomy. Journal of Bone and Joint Surgery 52B: 746--756. Mizutani H, Engleman RW, Kinjoh K et al (1993) Prevention and induction of occlusive coronary vascular disease in autoimmune (W/B) F, mice by haploidentical bone marrow transplantation: possible role for anticardiolipin autoantibodies. Blood 82: 3091-3097. Morton JI & Siegel BV (1974) Transplantation of autoimmune potential I. Development of antinuclear antibodies in H2-histocompatible recipients of bone marrow from New Zealand Black mice. Proceedings of the National Academy of Sciences of the USA 71:2162-2165. Muirden KD (1975) Periarticular bone lesions in rheumatoid arthritis. Scandinavian Journal of Rheumatology 4 (supplement): 8. Nakagawa T, Nagata N, Hosaka Net al (1993) Prevention of autoimmnne inflammatory polyarthritis in male New Zealand Black/KN mice by transplantation of bone marrow cells plus bone (stromal cells). Arthritis and Rheumatism 36: 263-268. Ochi T, Hakamori S-I, Adachi M e t al (1988) The presence of a myeloid cell population showing strong reactivity with monoclonal antibody directed to difucosyl type-2 chain in epiphyseal bone marrow adjacent to joints affected with rheumatoid arthritis (RA) and its absence in the corresponding normal and non-RA bone marrow. Journal of Rheumatology 15: 1609-1615. Owaki H, Ochi T, Yamasaki K et al (1989) Elevated activity of myeloid growth factor in bone marrow adjacent to joints affected by rheumatoid arthritis. Journal of Rheumatology 16: 572-577. Owaki H, Yukawa K, Ochi T et al (1991) FACS analysis of myeloid differentiation stages in epiphyseal bone marrow, adjacent to joints affected with rheumatoid arthritis. Scandinavian Journal of Rheumatology 210:91-97. Pearson CM & Wood FD (1964) Passive transfer of adjuvant arthritis by lymph node or spleen cells. Journal of Experimental Medicine 120: 547-560. Pincus T (1988) Disappointing long term outcomes despite successful short term clinical trials. Journal of Clinical Epidemiology 41: 1037-1041. Schwieterman WD, Wood GM, Scott DE et al (1992) Studies of bone marrow progenitor cells in lupus-prone mice. I. NZB marrow cells demonstrate increased growth in Whitlock-Witte culture and increased splenic colony-forming unit activity in the Thy-1 ~ lineage- population. Journal of Immunology 148: 2405--2410. Seitz M, Deimunn W, Gram Net al (1982) Characterization of blood mononnelear cells of rheumatoid arthritis patients: I-depressed lymphocyte proliferation and prostanoid release from monocytes. Clinical Immunology and lmmunopathology 25: 405--416. Seitz M, Swicker M, Pichler W & Gerber N (1992) Activation and differentiation of myelomonocytie ceils in rheumatoid arthritis and healthy individuals---evidence for antagonistic in vitro regulation by interferon-T and tumor necrosis factor r granulocyte monocyte colony stimulating factor and interleukin 1. Journal of Rheumatology 19: 1038-1044. Sheridan WP, Begley CG & Juttner CA (1992) Effective peripheral blood progenitor ceils mobilised by filgrastim (G-CSF) on platelet recovery after high dose chemotherapy. Lancet 339: 640644.
Slavin S (1993) Treatment of life threatening autoimmnne diseases with myeloabtative doses of
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immunosuppressive agents-----experimental background and rationale for ABMT. Bone Marrow Transplantation 12: 85-88. Stone RM (1994) Myelodysplastic syndrome after autologous transplantation for lymphoma: the price of progress? Blood 83: 3437-3440. Tamura T, Kanamofi H, Yamazaki E et al (1994) Cold agglutinin disease following aliogeneic bone marrow transplantation. Bone Marrow Transplantation 13: 321-323. Thomas D, Gallus AS, Brooks PM et al (1984) Thrombokinetics in patients with rheumatoid arthritis with D-penicillamine. Annals of the Rheumatic Diseases 43: 402--406. Thomas AE, Paterson J & Pretice HG (1987) Haemorrhagic cystitis in bone marrow transplantation patients: possible increased risk associated with prior busulphan therapy. Bone Marrow Transplantation 1: 347-355. Tomita T, Kashiwagi N, Shimaoka Y et at (1994) Pbenotypic characteristics of bone marrow cells in patients with rheumatoid arthritis. Journal of Rheumatology 21:1608-1614. van Bekkum DW (1993) BMT in experimental autoimmune diseases. Bone Marrow Transplantation 11: 183-187. van Bekkum DW, Kinwel-Bohre EPM, Houben PFJ & Knaan-Shanz~r S (1989) Regression of adjuvant-induced arthritis in rats following bone marrow Iransplantation. Proceedings of the National Academy of Sciences of the USA 86:1090-1094. van Gelder M, Kinwel-Bohre EPM & van Bekkum DW (1993) Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneie BMT. Bone Marrow Transplantation 1: 233-241. Vieten G, Hadarn MR, DeBoer Het al (1992) Expanded maerophage precursor populations in BXSB mice: possible reason for increasing monocytosis in male mice. Clinical Immunology and lmmunopatho logy 65:212-218.
Auto-immune diseases such as systemic lupus erythematosus (SLE), scleroderma and rheumatoid arthritis (RA) cause significant morbidity and mortality (Pincus, 1988; Fessler and Boumpas, 1995) and, although modem aggressive treatments may suppress disease activity in many cases, few if any complete cures for these diseases are reported. Over the last decade a more aggressive approach to these conditions, with the use of multiple immunosuppressive drugs given at an early stage in the disease, have been shown to be beneficial in diseases such as lupus renal disease (Klippel, 1990), but whether this approach significantly improves long-term outcome in rheumatoid arthritis is as yet unclear. The use of specific cytokine blockade has heralded a new direction in the management of rheumatoid arthritis and has recently been shown to be successful in the short term (Elliott et al, 1994). Whether this approach will sustain remission is yet to be proven. Our relative impotence in terms of management of these conditions demands a re-think of the aetiopathogenesis of these diseases and their treatment. SCIENTIFIC BASIS Dysregulation in autoreactive lymphocytes and bone marrow stem cells
Lesions in auto-immune diseases contain mature haemopoietic cells, such as lymphocytes and macrophages, which obviously play key roles in the pathogenesis. For example, they can be involved in the recognition and destruction of target tissue, and can be a source of many potential mediators of local immune and inflammatory reactions, such as cytokines, enzymes, free radicals etc. Whether auto-antigens are primarily responsible as triggers for the initial phase of disease or become significant in later stages due to, for example, cross-reactivity with an aetiological agent or to expression as a result of tissue damage, is a matter that is still widely debated. Bailli~re's Clinical Rheumatology673 Vol. 9, No. 4, November 1995 ISBN 0--7020-2076-1
Copyright 9 1995, by Bailli6re Tindall All fights of reproduction in any form reserved
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In adults, haemopoietic cells derive from precursor cells in the bone marrow by proliferation and differentiation. Auto-immune diseases are usually considered as arising from some type of immune dysfunction. There are cases of animal models where disease can be transferred by mature lymphocytes. Examples of such disease transfer into recipient animals include those where arthritis and experimental allergic encephalomyelitis (EAE) can be passed with spleen cells or cloned T cells from symptomatic animals to normal syngeneic ones (Pearson and Wood, 1964; Matsumoto and Fujiwara, 1988). Since the thymus has a significant role in the positive and negative selection of T cells and is apparently involved in the deletion of autoreactive clones, it has been considered that the aetiopathogenesis of both systemic and organ-specific auto-immune diseases could be attributed to defects in the thymus. However, there are many cases with animal studies which suggest that the auto-immune diseases originate from defects that reside in haemopoietic stem cells since some of the abnormalities of mature lymphocytes are transferrable with bone marrow cells (Morton and Siegel, 1974; Akizuki et al, 1978; Ikehara et al, 1990). In a number of murine models of auto-immune disease, such as lupus and insulin-dependent diabetes, there is one common feature of the mouse strains which develop disease--their pluripotent haemopoietic stem cells carry the information for the auto-immune phenotype which is ultimately expressed by more mature cells (Ikehara et al, 1990; Schwieterman et al, 1992). In other words, the auto-immune tendencies appear to be encoded in the cellular genome and are not directly dependent on the milieu of the surrounding tissue in which the stem cells expand and differentiate. It is also possible that the enhanced stem cell hyperplasia evident in some of the models might act to amplify and worsen the ongoing pre-existing auto-immune phenomena by supplying increased numbers of lymphocytes and monocytes, as well as their products (Schwieterman et al, 1992; Vieten et al, 1992). Granulocyte-macrophage colony-stimulating factor (GMCSF) has been shown to activate monocytes to express major histocompatability complex (MHC) antigens and adhesion molecules, and promote pro-inflammatory cytokine production (Gasson, 1991). Field and Clinton (1993) have recently demonstrated that significantly more monocytes from patients with rheumatoid arthritis express GM-CSF receptor than do those from healthy volunteers or patients with osteoporosis. Since GM-CSF is produced by synovial cells in RA, the continuing inflammatory response could be enhanced by activation of the entering monocytes. Bone and rheumatoid arthritis
In rheumatoid arthritis (RA), it is widely assumed that the development of the synovial pannus, as a vascular granulation tissue, is the sole primary event by which cartilage is first destroyed. However, in synovectomy studies performed a number of years ago on early RA lesions, proliferative changes in the periosteum and perichondrium were observed in the absence of a 'pannus' (Mills, 1970); it was suggested that the pannus was an endresult rather than a cause of the cartilage breakdown. In early RA cases
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again, even when there was no macroscopic evidence of cartilage damage, a marked cellular reaction in the periosteum deep to the synovial layer was noted (Muirden, 1975). Osteoclastic and osteoblastic reactions were seen on the marrow surface of trabeculae. More recently there have been other reports of abnormalities in bone marrow cells of RA patients, such as abnormal myeloid cells (Ochi et al, 1988), enhanced monocyte DNA synthetic activity (Dreher et al, 1986), higher than normal numbers of mononuclear cells positive for HLA DR and CD14 (Seitz et al, 1992), abnormally high myeloid growth factor activity and myeloid precursor numbers in bone marrow next to affected joints (Owaki et al, 1989; Kotake et al, 1992), increased numbers of mononuclear cells in the iliac bone marrow (Tomita et al, 1994) and differences in T-cell subsets suggestive of immunological activation (Doita et al, 1990). It has therefore been considered that severe RA is associated with an aberrant proliferation of bone marrow myeloid cells adjacent to affected joints (Ochi et al, 1988; Owaki et al, 1991); in addition, it has been claimed that changes in the iliac bone marrow point to an important role of systemic bone marrow in the progression of RA (Tomita et al, 1994). The bone marrow abnormalities listed above presumably reflect enhanced haemopoietic activity there as part of an immune or chronic inflammatory reaction associated with the development of RA. Alternatively, there could be an inherent dysregulated haemopoiesis of unknown aetiology analogous to the murine auto-immune models described above. There are reports that about 30% of patients with RA have peripheral blood monocytosis (Buchan et al, 1985) and that the mononuclear cell population contains 50% monocytes, compared with 23% monocytes in healthy controls (Seitz et al, 1982). Also, thrombocytosis is common in acute and severe rheumatoid disease. Slow-acting anti-arthritic drugs and bone marrow
Drugs such as gold compounds, o-penicillamine, antimalarials and methotrexate are given to slow down or halt RA progression. Several mechanisms to account for the therapeutic benefit of these drugs have been suggested, including immunological and anti-inflammatory effects. During treatment with these disease-modifying drugs, the white blood cell count is monitored routinely. A trend towards a fall in white cell or platelet numbers is an indication to stop treatment or lower the dose and one of the more serious effects of these drugs is leukopenia. A reduction in myeloid progenitor cell numbers in the bone marrow, coinciding with leukopenia, has been reported for a RA patient treated with gold thiomalate (Howell et al, 1975). It has been proposed that the penicillamine-induced thrombocytopenia in RA patients is due to bone marrow suppression (Thomas et al, 1984) and there is data to show that human myeloid bone marrow progenitor cells in vitro are extremely sensitive to the growth inhibitory effects of diseasemodifying drugs (Hamilton and Williams, 1985, 1987). On the basis of observations such as these, it has been proposed that disease-modifying antirheumatic drugs act by inhibiting myelopoiesis thus reducing slowly
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the numbers of inflammatory cells present in lesions (Hamilton and Williams, 1985, 1987; Hamilton, 1993). In other words, their efficacy may in fact be due to their myelotoxic or bone marrow suppressive activities. Bone marrow transplantation
The above discussion has presented some evidence for the involvement of autoreactive lymphocytes in auto-immune disease, for a defect in the bone marrow stem cells in hereditary experimental auto-immune disease, and for the involvement of altered bone marrow in RA patients. Unless the pathogenic population of autoreactive lymphocytes is depleted in auto-immune disease, established disease will be self-sustaining and intervention with agents such as the new cytokines or monoclonal antibodies may have to be given for life. Scientifically speaking, such a depletion is feasible with allo-bone marrow transplantation (BMT); the results from such approaches will be presented below. Alternatively, it has been proposed that if mature autoreactive lymphocytes could be eliminated and the immune system allowed to redevelop from autologous precursors, the chance of redeveloping a particular auto-immune disease should approach the rate of incidence in unaffected monozygotic twins (Carson, 1992). This idea is more likely to be relevant if any aetiological agent(s) relevant to an auto-immune disease were present early in life and therefore would not influence the development of the reconstituted immune system. Given the recent knowledge regarding lymphocyte differentiation and availability of cytokines controlling such differentiation, this type of therapeutic approach is now feasible. Some experimental support for the possibility of successful clinical autologous BMT is the perhaps surprising result that adjuvant arthritis and EAE could be resolved by immune ablation followed by autologous stem cell transplantation (van Bekknm, 1993). As mentioned, in a disease such as RA, there may also be defects in cells of the myeloid lineages, such as the macrophages, which could be inappropriately 'activated' to produce inflammatory mediators. In fact, the type of cell in the rheumatoid synovium which correlates best with the degree of joint erosion is the macrophage. A similar rationale for the value of their depletion, as enunciated above for the depletion of autoreactive lymphocytes, can be applied. Perhaps the ablation portion of any BMT therapy used successfully in RA disease (Lowenthal et al, 1993) is in fact already occurring in a mild way, as pointed out above, during treatment with disease-modifying drugs (Hamilton, 1993). ANIMAL MODELS Both allogeneic and autologous bone marrow transplantation has been shown to modify and, in some instances, reverse a variety of animal models of auto-immune disease (Table 1). van Bekkum et al (1989) reported the regression of adjuvant induced arthritis in rats and showed that tmns-
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plantation of syngeneic bone marrow was as effective as allogeneic bone marrow from rat strains not susceptible to induction of adjuvant arthritis. The treatment was most effective when applied shortly after the clinical manifestation of the arthritis occurred, i.e. within 4-7 weeks after administration of mycobacterium tuberculosis. Nakagawa et al (1993) demonstrated that auto-immune polyarthritis could be prevented in male New Zealand black mice prone to developing this disease after transplantation with bone marrow cells (which will recruit stromal cells) plus bone from normal donors. They had previously shown that bone marrow transplantation alone was not successful in treating these diseases but that bone marrow cells plus bone transplantation rendered the joint bones radiologically and histopathologically normal and the mice demonstrated decreased production of anti-single-stranded DNA antibodies and rheumatoid factors at 8-12 months of age. Table 1. Animal models demonstrating BMT effect on disease.
Model
Result
Reference
Adjuvant arthritis (rats) Auto-immune polyarthritis (mice) Auto-immune nephritis and coronary vascular disease (mice) SLE (mice) Diabetes (nude mice) Diabetes (nude mice) Auto-immune encephalomyelitis (mice) Anto-immune encephalomyelitis (mice)
Regression of disease Prevention Prevention
van Bekkum et al (1989) Nakagawa et al (1993) Mizutani et al (1993)
Prevention Prevention Prevention Prevention Reversal
Marmot (1993) lkehara et al (1985) Georgiou et al (1993) lkehara et al (1985) van Gelder et al (1993)
Mizutani et al (1993) studied auto-immune mice (W/B) who developed systemic auto-immunity involving the production of auto-antibodies, thrombocytopenia, lupus nephritis and coronary vascular disease with myocardial infarction. Transplantation of T-cell depleted marrow gave a 90% protection in the recipients from the development of lupus and no mice developed coronary vascular disease. A number of other animal studies have shown that auto-immune disease including spontaneous lupus in mice can be prevented by bone marrow transplantation (Marmot, 1993). Diabetes, which occurs spontaneously in the nude mouse model and which is due to an auto-immune T-cell-mediated insulinitis, can be both transferred from the nude mouse to normal recipients and prevented by bone marrow transplantation of the nude mice (Ikehara et al, 1985; Georgiou et al, 1993). Another auto-immune disease---experimental allergic encephalomyelitis (EAE)---can also be shown to be prevented and the clinical manifestations reversed by allogeneic, syngeneic and autologous haemopoietic stem cells (Karussis et al, 1993; van Gelder et al, 1993). Levite et al recently showed that experimental SLE can be induced in mice by immunization with either a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id) or with a mouse monoclonal antiidiotypic antibody specific for the 16/6 Id. Susceptibility to the induction of
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the experimental SLE is genetically determined and not linked to the MHC. The susceptibility of bone marrow chimeras of different donor host combinations to the induction of SLE has been studied and high levels of anti 16/6 Id and anti-ss-DNA antibodies are induced in some of these animals but not in others. Low levels of the anti 16/6 Id and anti-ss-DNA antibodies are produced by the C57 BL/6--->BALB/c chimeras immunized with 16/6 Id. Following allogeneic BMT such chimeras will produce high levels of antibodies to a T-cell-dependent antigen, suggesting that the production of SLE-related autoantibodies is controlled by donor type BM derived cells and not by host type cells in the thymic stroma. These animal experiments show clearly that allogeneic, syngeneic and autologous transplantation can be used to both transfer these diseases and prevent, or at least modify, their immunopathology. These data suggest that the pluripotential bone marrow cells may have an important role to play in these diseases and provide the basis for experimentation of these interventions in humans. CLINICAL BLOOD AND BONE M A R R O W TRANSPLANTATION It is now more than 35 years since E. D. Thomas and co-workers reported that large quantities of bone marrow could be safely infused into humans and that transient engraftment of haemopoietic cells was possible. Since then, clinical bone marrow transplantation has become widely utilized and is capable of curing a number of acquired and congenital disorders of the haemopoietic, immune and metabolic systems (Atldnson, 1994; Forman et al, 1994). It is now beginning to be applied to solid tumours such as breast and testicular cancer. Haemopoietic stem cells are likely also to be a prime vehicle for gene therapy. The source of haemopoietic stem cells for transplantation may be either an HLA-identical family member or unrelated volunteer (allogeneic transplantation), an identical twin (syngeneic transplantation) or from the recipient himself or herself (autologous transplantation) (Table 2). In the latter situation the marrow should not overtly be involved by disease at the time of harvest. This may have implications for the treatment of autoimmune disease. Table 2. Types of bone marrow transplants. Type
Source of haemopoietic stem cells
Autologous Syngeneic Allogeneic HLA-identical family member
Patient Identical twin
HLA-non-identical family member HLA-identical unrelated donor
Usually HLA-identical sibling (occasionally parent, child, other) Family member matched for five of the six HLA-A, -B and -DR antigens Unrelated volunteer
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Blood stem cells are widely utilized instead of marrow stem cells as a source of haemopoietic stem cells in autologous transplantation and increasingly in allogeneic transplantation. This is because blood cells can be extracted from the circulation in huge numbers using a cell separator machine after their mobilization from the marrow cavity, either by chemotherapy or haemopoietic growth factors or both. They can then be cryopreserved while the patient receives the high-dose chemotherapy or chemoradiotherapy treatment aimed at ablating the underlying disease. Once this is completed the blood stem cells can be thawed and re-infused into the recipient to allow recovery from the marrow ablative treatment. The increased number of haemopoietic stem cells present in a blood stem cell transplant compared to a marrow transplant results in accelerated recovery of both neutrophil and platelet counts post transplant, rendering the procedure safer with less risk of infection and haemorrhage respectively (Table 3) (Sheridan et al, 1992).
Table 3. Source of haemopoietic stem cells. Source
Advantages
Disadvantages
Marrow
No mobilization required
General or spinal anaesthetic; short inpatient admission Slower recovery of blood count in recipient
Blood
No anaesthetic; outpatient procedure Faster recovery of blood count in recipient May have less tumour cell contamination than bone marrow Can be obtained from patient with marrow damage (e.g. previous pelvic radiotherapy)
TECHNIQUE The technique of haemopoietic stem cell transplantation (blood or marrow) is relatively simple. It involves first the identification of a suitable source of haemopoietic stem cells. If this is from the recipient (autologous transplant), these are usually harvested either from the blood or from the marrow and cryopreserved in liquid nitrogen at -179~ They can be kept at this temperature indefinitely. If the donor is an HLA-compatible normal person (relative or unrelated volunteer donor), the marrow or blood haemopoietic stem cells are normally harvested and infused fresh on the day of transplant. The principle behind marrow transplantation is that very-high-dose chemotherapy or chemoradiotherapy (including total body irradiation) is given to ablate the underlying disease (Table 4). Diseases primarily treated by allogeneic transplantation or by autologous transplantation are shown in Table 5. For allogeneic transplantation it is also necessary to eradicate the recipient's immune system so that he or she will accept the incoming donor graft.
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J. A. HAMILTON ET AL Table 4. Technique of haemopoietic stem cell transplantation. 1. High-dose chemotherapy or chemoradiotherapy 2. Intravenous infusion of haemopoiefic stem cells
Table 5. Diseases treatable by haemopoietic stem cell transplantation. AML ALL CML CLL
Myelodysplasia Myeloma
Myelofibrosis Hodgkin's disease
Non-Hodgkin's disease Breast cancer Testicular cancer Ovarian cancer
Childhood solid tumours Severe aplastic anaemia Fanconi's anaemia Thalassemia major
Severe combined and other congenital immune disorders
Allogeneic transplant
Autologous transplant
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes
No No No No Yes Yes Yes Yes
Experimental Experimental No Yes No Yes Yes Yes Yes
Experimental Yes No No No No
AML = acute myeloid leukaemia; ALL = acute lymphoblastic leukaemia; CML = chronic myeloid leukaemia; CLL = chronic lymphatic leukaemia.
As a consequence of this high-dose chemotherapy/chemoradiotherapy the recipient's marrow is ablated and such high dosage cannot be used unless a source of haemopoietic stem cells is available afterwards to allow marrow repopulation and blood count recovery. M A R R O W HARVEST This is normally performed under general anaesthetic or under spinal anaesthesia. Marrow is aspirated by needle punctures into the posterior superior iliac crests; 5 ml of marrow is aspirated each time until approximately 3 x 108 nucleated marrow cells/kg recipient weight have been obtained. This figure allows for rapid allogeneic engraftment. ABO incompatibility between donor and recipient is not a barrier to allogeneic transplantation, but if a major ABO difference exists between the two, the recipient will normally undergo plasmapheresis to remove circulating isoagglutinins that would otherwise haemolyse the red cells in the incoming donor marrow. Additionally, the marrow itself is depleted of red cells prior to its infusion into the recipient.
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BLOOD STEM C E L L HARVEST If the source of stem cells is the blood rather than the marrow, blood stem cells are removed in the mononuclear cell component by a cell-separator machine. This procedure is carried out as an outpatient usually on several consecutive days and involves the blood stem cell donor having an intravenous cannula in each ann. The blood from one arm is taken to the machine which centrifuges the blood, separates the red cells from white cells and scoops the mononuclear cells into a bag. They are then cryopreserved. Red cells and plasma are returned to the recipient through the cannula in the opposite arm. Only minimal numbers of stem cells circulate in the normal basal state. Therefore, for blood stem cell harvest, marrow cells have to be mobilized into the blood stream. This is done either by use of a haemopoietic growth factor given to the blood stem cell donor for 4-7 days prior to blood stem cell harvest--usually granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytotoxic chemotherapy is an additional means of mobilizing marrow cells into the circulation and the highest numbers of blood stem cells are obtained using a combination of cytotoxic chemotherapy and a haemopoietic growth factor. Cytotoxic chemotherapy cannot of course be given to normal tissue compatible marrow donors, and in such circumstances blood stem cells are mobilized by haemopoietic growth factor administration. COMPLICATIONS OF A L L O G E N E I C M A R R O W OR BLOOD STEM CELL TRANSPLANTATION (Table 6)
Early post-transplant In the first 2-3 weeks after either allogeneic or autologous stem cell transplantation, the recipient's blood count is ablated by the nigh-dose chemotherapy/chemoradiotherapy, and he or she remains neutropcnic and thrombocytopenic for 10-20 days. Most recipients have an episode of febrile neutropenia which in the majority resolves satisfactorily with the early use of intravenous antibacterial antibiotics (Hughes et al, 1990), Table 6. Complications of haemopoietic stem cell transplantation.
Type of transplant
Early
Late
Allogeneic and autologous
Pancytopenia/infection Gastrointestinal Mucosal damage Haemorrhagic cystitis Hepatic veno-oeelusive disease Interstitial pneumonitis Alopecia
Infertility
Allogeneic
Acute graft-versus-host disease
Secondary malignancy Cataracts Growth stunting (children) Pubertal delay (children) Secondary malignancy Chronic graft-versus-host disease
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Also in the first 2-3 weeks post-transplant, the oropharyngeal and gastrointestinal mucosae are damaged by the high-dose chemotherapy/ chemoradiotherapy, producing ulceration and discomfort. Anorexia is universal, with some degree of discomfort, nausea, vomiting and diarrhoea. This situation is normally manageable with the use of opiate analgesia and intravenous total parenteral nutrition.
Unusual complications due to the high-dose chemotherapy/ chemoradiotherapy Rare complications that usually occur within the first few weeks post-transplant include haemorrhagic cystitis due to the effect of either high-dose cyclophosphamide, busulphan, etoposide or ifosfamide on the urothelium. The risk of this can be minimized by high-dose intravenous hydration during administration of the cytotoxic chemotherapy. Another complication of the high-dose chemotherapy is hepatic veno-occlusive disease due to intimal injury of the small hepatic venules. This can be minimized with the use of intravenous heparin during the period of chemotherapy administration and the first 3 weeks post-transplant, which reduces the risk of secondary coagulation on the damaged intima. Another rare complication of the high-dose cytotoxic chemotherapy is chemical pneumonitis, usually manifesting as interstitial pneumonitis. This may have to be diagnosed by lung biopsy to distinguish it from cytomegalovirus or Pneumocystis carinii pneumonia. Chemical pneumonitis often responds to prednisone therapy (Meyers et al 1982; McDonald et al, 1984; Thomas et al, 1987).
Late post-transplant A rare late complication of high-dose chemoradiotherapy and stem cell transplantation is secondary malignancy. This occurs more commonly after autologous than allogeneic transplantation. The commonest type of malignancy is myelodysplasia/acute myeloid lenkaemia which may occur in up to 10% of recipients of autologous transplants by 10 years post transplant (Stone, 1994). One complication of allogeneic transplantation that does not occur with autologous transplantation is graft-versus-host disease. This is mediated by mature donor T cells present in the donor inoculum which recognize histocompatibility antigen disparities present in the recipient and absent in the donor. It is usually preventable by a combination of cyclosporin and methotrexate immune suppression. This usually needs to be given for 6-12 months after allogeneic transplantation. Prothymocytes that are generated from the donor haemopoietic stem cells appear to be tolerized by transit through the recipient thymus, and immune suppression can usually be ceased relatively early after an allogeneic marrow transplant (in contradistinction to allogeneic solid organ transplants).
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EFFICACY OF H A E M O P O I E T I C STEM CELL TRANSPLANTATION The cure rate of marrow transplantation depends on the underlying disease, the status of the disease at the time of transplant, the source of haemopoietic stem cells and the physical condition of the recipient at the time of transplant (Table 7). Representative outcomes in terms of treatment-related mortality, relapse rate and disease-free survival rate for a number of different diseases and types of transplants are shown in Table 8. The range of disease in which BMT is beneficial and the mortality and morbidity rate is changing each year. Table 7. Factors affecting outcome of transplant.
Disease for which transplant is being performed Performance status of the recipient Degree of donor-recipient histocompatibility (allogeneie) Status of disease at the time of transplant Age of recipient
Table 8. Disease-free survival after haemopoietic stem cell transplantation'.
Disease
Allo transplant
Auto transplant
AML in first complete remission AML beyond first complete remission CML in first chronic phase CML beyond first chronic phase Hodgkin's disease in first relapse High-risk breast cancer Severe aplastic anaemia Thalassaemia major
70% 20% 80% 20% Insufficient data Not done 75% 70-95%
45% 20% < 5% 0 55% 70% Not done Not done
"For abbreviations see footnote to Table 5.
HUMAN EXPERIMENTS Bone marrow transplantation has been used as a treatment for gold-induced thrombocytopenia in patients with rheumatoid arthritis (Adachi et al, 1987) and there are a number of cases in the literature where bone marrow transplantation done for other reasons (co-existing neoplastic disease or drug-induced aplasia) has produced a remission in patients with rheumatoid arthritis. The majority of these patients have been reported to have longterm remissions, although there are instances where the disease has returned some years later associated with a rise in the rheumatoid factor. Other auto-immune diseases such as psoriasis and ulcerative colitis have also been shown to go into sustained remission following bone marrow transplantation (Eedy et al, 1990; Liu Yin and Jowitt, 1992). Recently a case of auto-immune mixed cryoglobulinaemia with vasculitis and nephritis was successfully treated with myeloablating immunosuppressive treatment followed by autologous stem cell transplantation (Slavin, 1993).
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On the other hand, cold-agglutinin disease has been reported following aUogeneic bone marrow transplantation (Tamura et al, 1994) and there are a number of cases where insulin-dependent diabetes has been transferred from donors to recipients (Lampeter et al, 1993), Data from animal models suggest that syngeneic transplantation will significantly modify auto-immune disease, although this has not yet been attempted in humans. The lower mortality and morbidity of this form of transplantation makes it an attractive option in these non-fatal conditions. The critical question is whether the stem cells are already affected by the disease. One might argue that the genetic susceptibility to developing rheumatoid arthritis or SLE may well continue even if the disease is put into remission but it must be remembered that the genetic component is but one of a number of risk factors in these diseases. In developing a therapy that has the potential to cure these auto-immune diseases, it will be important to use them early in the disease before damage to vital organs has occurred. Identification of these patients who will have a bad outcome is now becoming a reality at least in diseases such as rheumatoid arthritis. Gough et al (1994) have recently demonstrated that the presence of conserved base sequences in the third hypervariable region of the DrB1 gene and the presence of rheumatoid factor provide a relative risk of eight for the development of erosions at 1 year. The presence of DW4 and DW14 was an even more powerful predictor of erosion formation. BMT will never be a treatment for all auto-immune diseases, but the potential for cure, coupled with our increasing ability to identify those patients with auto-immune disease who are at high risk of doing particularly badly, demand that we carefully evaluate the procedure and the outcome. BMT for auto-immune disease remains an experimental treatment, but its potential for cure of these conditions requires that it be carefully evaluated. International collaboration is required to develop guidelines for the selection of patients and for the procedure, especially the type of transplantation to be carded out and the immunosuppressive regimen to be given. No single unit is going to have sufficient patients to provide meaningful data so that international co-operation is vital to evaluate this potentially curative therapy rapidly.
Acknowledgements The support of the Clive and Vera Ramaciotti Foundation is acknowledged.
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