Autoimmunity following haematopoietic stem-cell transplantation

Best Practice & Research Clinical Haematology Vol. 20, No. 2, pp. 349e360, 2007 doi:10.1016/j.beha.2006.09.008 available online at http://www.sciencedirect.com

14 Autoimmunity following haematopoietic stem-cell transplantation Thomas Daikeler*

MD

Consultant

Alan Tyndall

MD

Professor Department of Rheumatology, University of Basel, University Hospital Basel, Petersgraben 4, CH-4058 Basel, Switzerland

Autoimmunity after stem-cell transplantation has been observed over decades. Evidence comes from single case reports or small series. Autoimmune phenomena are known in both the autologous and the allogeneic settings, irrespective of the graft source. Most publications deal with autoantibody production after transplantation; more rarely, the appearance of the associated autoimmune disease is reported. Autoimmune thyroid disease and autoimmune cytopenias are most often described. Homeostatic expansion after transplantationinduced lymphopenia is thought to be a trigger for loss of self-tolerance and proliferation of autoreactive T-cells in these patients. With allogeneic haematopoietic stem-cell transplantation, adoptive transfer of autoimmune disease has been shown, raising the issue of graft quality. Many of the clinical and laboratory features of graft-versus-host disease (GvHD), especially in its chronic form, resemble those of autoimmune diseases, and the pathophysiological mechanisms are similar. Prospective data for a better understanding of autoimmunity and ‘altered’ immunity after stem-cell transplantation are needed. Key words: haematopoietic stem-cell transplantation; autoimmunity; post-transplantation; adoptive transfer.

Haematopoietic stem-cell transplantation (HSCT) has a major impact on the immune system, sometimes as an intended effect such as treatment of autoimmune disease1, but more often as an unwanted side-effect following treatment of malignancies and * Corresponding author. Tel.: þ41 61 265 2709; Fax: þ41 61 265 3422. E-mail address: [email protected] (T. Daikeler). 1521-6926/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

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inborn errors of metabolism.2 Apart from the known early and late side-effects, such as infections or secondary malignancies, the emergence of autoimmune processes after HSCT is being recognized more frequently. It is often unclear whether this emerging ‘altered immunity’ is truly autoimmunity, and whether it is due to the whole HSCT procedure or to one or more of its individual components. This review aims to examine the possible pathophysiological mechanisms, to summarize the known data in both animals and humans, and to suggest future strategies to better understand and manage the problem. At the centre of the issue is the concept of homeostatic expansion after conditioning-induced lymphopenia in HSCT and its consequences for the immune system. Further issues are transfer of autoimmunity from the donor to the recipient, and autoimmunity associated with the use of different treatment modalities for conditioning. In addition, some post-HSCT infections, such as the EpsteineBarr virus (EBV) lymphoproliferative syndrome, may mimic autoimmune diseases, making the interpretation of anecdotal observations difficult. HOMEOSTATIC EXPANSION OF LYMPHOCYTES Homeostatic expansion describes a process of vigorous T-cell expansion in a host with acquired lymphopenia. This may be caused by infection or stress, or may be iatrogenic through lymphoablative conditioning before HSCT. Homeostatic expansion is a process which affects na€ıve and antigen-experienced T-lymphocytes, and in some studies there is a suggestion that the resulting expansion from the memory T-cell pool favours development of autoimmunity.3 It has been shown in the mouse model that for homeostatic expansion, a tight binding of the major histocompatiblity complex (MHC) plus self antigen with T-cell receptor (TCR) complex is required.4 This favours the expansion of pre-existing autoreactive T-cell clones due to a temporary suspension of mechanisms aimed at maintaining self-tolerance and can lead to autoimmune reactions. The exact mechanism leading to this loss of self-tolerance is still unclear. In a murine cardiac allogeneic transplant model, regulatory (Treg) T-lymphocytes were ablated more efficiently than memory T-cells, resulting in a resistance to tolerance induction.5 However, another group has shown in another murine model that Tregs are relatively resistant to a polyclonal anti-lymphocyte serum (ALS), accounting for some of the immunosuppressive effect of ALS in clinical settings.6 A similar phenomenon has been suggested in humans following autologous HSCT for juvenile idiopathic arthritis treatment.7 Clearly the emergence of autoimmunity will depend on the balance between putative autoreactive and regulatory lymphocyte populations, which will be different in each model or patient experiencing the perturbation. Homeostatic expansion of lymphocytes in the animal model The association of lymphopenia and autoimmunity is also described in the non-obese diabetic (NOD) mouse model. NOD mice, especially the females, have reduced numbers of T-cells and may develop autoimmunity as a result of a ‘second hit’ such as increased interleukin-21 (IL21). This is not shown for those non-lymphopenic mouse strains not developing autoimmune diabetes. Transfusion of high numbers of purified CD4þ T-cells from mice of the same strain prevents diabetes development in NOD mice.8 In the K/BxN mouse model for rheumatoid arthritis, CD4þ T lymphopenia is also present. These cells are expanded in the early clinical phase of the disease

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and acquire the memory phenotype of homeostatically expanding cells. Syngeneic transfer of CD4þ T-cells in these mice reverses lymphopenia and inhibits the development of arthritis symptoms.9 Homeostatic expansion in infection-induced lymphopenia In humans, lymphopenia is often associated with viral infection both as cause and effect. The most profound CD4þ T-lymphopenia is seen in patients infected with HIV, and indeed HIV infection is associated with autoimmunity. This is often seen in association with the immune reconstitution inflammatory syndrome (IRIS) after the introduction of antiviral treatment.10 Moreover, there is evidence that autoimmune diseases such as sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus or Graves disease occur after immune reconstitution due to effective antiretroviral therapy.11 Therefore, as with the animal data, the data from virus-induced lymphopenia in patients support the concept of homeostatic expansion-associated autoimmunity. Homeostatic expansion in patients following HSCT In the course of HSCT, lymphopenia is induced by conditioning therapy. The resulting ‘empty space’ in the lymphoid organs is occupied by expansion of those lymphocytes surviving induction therapy and/or those reinfused with the graft product after HSCT. This is the case in autologous HSCT. In the allogeneic setting, remaining lymphocytes after HSCT ideally do not expand if full chimerism is achieved. In these patients donor lymphocytes of the graft may undergo homeostatic expansion. However, in the case of non-myeloablative conditioning in allogeneic HSCT there might be not enough ‘empty space’ for homeostatic expansion. Nevertheless, immune reactivity against the host is also possible for allogeneic lymphocytes undergoing homeostatic expansion after HSCT. Complete functional reconstitution of the immune system after HSCT depends on different factors such as intensity of in vivo T-cell depletion through conditioning and T-cell depletion of the graft, and on host factors such as age and thymic function. De novo T-cell ontogeny can be delayed in these patients. The appearance of de novo thymic differentiated T-lymphocytes can be measured by T-cell receptor excision circles (TREC) DNA quantification. TRECs are episomal DNA molecules formed during T-cell receptor rearrangement occurring in the thymus.12 In six patients after autologous HSCT for autoimmune disease, TRECS appeared at a median of 16 (9e24) months after HSCT.13 This protracted disturbance of the T-cell repertoire was also observed in seven patients transplanted for systemic sclerosis.14 However, in a recent study of seven multiple sclerosis patients who had undergone autologous HSCT, immune reconstitution was eventually complete without relapse of disease.15 It is clear that the initial recovery of the T-lymphocyte count in the peripheral blood is due to homeostatic expansion and, depending on the T-cell subsets and prevailing conditions such as intercurrent infection, an autoimmune process may be set in train. IMMUNE DYSFUNCTION IN GRAFT-VERSUS-HOST DISEASE Graft versus host disease (GvHD) occurs after allogeneic HSCT and is due to a reactivity of donor lymphocytes against host tissue. Many of the clinical and laboratory features of GvHD, especially in its chronic form, resemble autoimmune disease. Indeed many of the pathophysiological mechanisms may be similar. The main difference is that

352 T. Daikeler and A. Tyndall

in GvHD the donor mature lymphocytes recognize antigens on host antigen-presenting cells and initiate host tissue destruction. This occurs because of genetic differences in major and/or minor histocompatibility genes between donor and recipient. As with de novo autoimmune disease, a failure of peripheral tolerance has been proposed as one mechanism responsible for acute GvHD progressing to its chronic form.16 In addition, a failure in the thymus to clonally delete host-reactive T-cells will also result in GvHD, and many patients receiving allogeneic HSCT have had thymic epithelial damage by radiation or direct attack by donor effector T-cells. In addition, many immunosuppressive drugs will impair clonal selection in the thymus. Although acute GvHD is becoming more amenable to prevention and treatment, chronic GvHD remains an unresolved issue in HSCT. Development of autoantibodies has long been recognized in GvHD17, but does not necessarily correlate with clinical autoimmune disease.18 The scleroderma-like syndrome seen with chronic GvHD has some important differences with idiopathic systemic sclerosis; Raynaud‘s features and pulmonary fibrosis are less striking, and the typical autoantibodies such as anti-topoisimerase 1 (Scl-70) and anticentromere are mostly absent, although this has been challenged.19 Recently autoantibodies activating the platelet-derived growth factor receptor have been described in both systemic sclerosis and chronic GvHD, bringing the two entities closer together mechanistically.20 SICCA syndromes resembling Sjoegren’s syndromes and chronic inflammatory liver disease are also common manifestations of chronic GvHD and may pose diagnostic confusion. GvHD is an expression of dysfunction of the specific immune system transferred to a genetically different host and has therefore to be clearly distinguished from ‘true’ autoimmune diseases. TRANSFER OF AUTOIMMUNITY Several case reports over the past decade have suggested that autoimmune disease may be transferred through HSCT from the donor to the recipient. Examples include adoptive transfer of psoriasis in a syngeneic HSCT21, as well as transfer of autoimmune thyroid disease22, coeliac disease23, insulin-dependent diabetes mellitus24, myasthenia gravis25, vitiligo26, and Crohn‘s disease.27 The latter is of major concern given the recent knowledge that the NOD2/CARD15 polymorphism associated with Crohn‘s disease28 imparts increased risk of GvHD gut disease.29 This emphasizes the important issue of ‘graft quality’ concerning selection of donor and long-term risk of autoimmune disease and other complications.30 Single case reports of adoptive transfer of autoimmunity through allogeneic HSCT are summarized in Table 1. Table 1. Case reports on autoimmune diseases transferred from donor to recipient. Autoimmune disease

Graft source

Reference

Psoriasis Psoriatic arthritis Coeliac disease Vitiligo Type 1 diabetes mellitus Autoimmune thyroiditis Crohn’s disease Myasthenia gravis

Syngeneic bone marrow Sibling bone marrow Sibling bone marrow Sibling bone marrow Sibling bone marrow Sibling peripheral stem cells Peripheral stem cells

[21] [57] [23] [26] [24] [22,39] [27] [25]

Autoimmunity following HSCT 353

However, to emphasize the complexity of the reconstituting immune system, a case report from Sweden showed that an autoimmune donor immune system was made tolerant in the new host. An acute myeloid leukaemia patient received an HSCT from his HLA-identical brother, who had systemic lupus erythematosus (SLE) and the typical lupus autoantibody to C1q. The recipient was initially negative for this antibody, but over the next 4 months it appeared then disappeared from his blood without him ever developing symptoms of SLE.31 In another case, adoptive transfer of rheumatoid arthritis also failed to occur following allogeneic HSCT for chronic myeloid leukaemia.32 Autoimmunity is clearly not 100 % determined in the haematopoietic stem cell; additional factors therefore are necessary for adoptive autoimmunity to occur. AUTOIMMUNITY AFTER HSCT Autoimmunity after HSCT is reported in the literature in several conditions: (1) the appearance of autoantibodies in recipients after HSCT and the development of epitope-specific autoantibody and/or T-cell memory-driven autoimmune disease after HSCT, most likely due to homeostatic expansion; (2) the transfer of autoimmunity from donor to recipient; and (3) the ‘altered immunity’ associated with graft versus host disease (GvHD). Moreover, autoimmunity may occur in direct relationship to one or more components of the conditioning regimen for HSCT. A major problem associated with HSCT is infection. In these complex patients, the differentiation between infection and autoimmunity can be confounding. Therefore ‘mimics’ of autoimmunity should be considered when assessing autoimmunity and HSCT (Table 2). Up till now, conclusive prospective trials to answer these questions have not been published. However, some evidence is emerging, mainly through case reports and small single-centre series. Autoantibodies after HSCT and their association to disease An increased incidence of autoantibodies after autologous, syngeneic and allogeneic HSCT is reported in the literature. Many of these autoantibodies e such as antinuclear antibodies (ANA) e are not associated with clinical symptoms, whereas others are in the context of autoantibody-mediated organ dysfunction such as autoimmune thrombocytopenia or thyroid dysfunction. It is now known that some highly specific autoantibodies e such as those against cyclic citrullinated peptide (CCP)33 in rheumatoid arthritis e may precede the first clinical manifestations of disease by up to 15 years. In the case of allogeneic or syngeneic HSCT these autoantibodies can be transferred through transfer of autoantibody-producing plasma cells from the donor to the recipient, or they develop de novo in the recipient as they may do in autologous transplanted patients. It should be noted also that a similar autoantibody production and organ dysfunction may occur after severe immunodepletion without HSCT. This has been reported in multiple sclerosis after Campath treatment when around one third of patients developed autoimmune thyroid disease.34 Autoimmune thyroid disease after HSCT In fact, autoimmune thyroid disease appears to be particularly prevalent after lymphoablative therapy, perhaps reflecting the high prevalence of autoimmune thyroid disease generally.35

354 T. Daikeler and A. Tyndall

Table 2. Symptoms of autoimmunity and warning signs. Symptom

Think of

Further investigations

Oligo/mono-arthritis

Infection (bacteria) Gout

Joint aspiration Blood culture

Polyarthritis

Infection Connective-tissue disease Rheumatoid arthritis GvHD

Clinical exam: skin rash Raynaud syndrome, other organs involved

Cytopenia

Alloantibodies AIHA/ITP Infection Drugs Thrombocytopenic purpura

ABO incompatibility Connective-tissue disease Check also for virus, tuberculosis, fungal infection ANA, virus (parvo B19, hepatitis B/C, rubella), RF CCP-ab Coombs, virus (herpes family, parvo B19) ANA Blood smear

ANA, antinuclear antibodies; RF, rheumatoid factor; CCP-ab, anti-cyclic citrullinated peptide antibodies; ITP, immune thrombocytopenia; AIHA, autoimmune haemolytic anaemia.

Impaired thyroid function after HSCT can be due to different mechanisms. It can be due to direct toxicity of the conditioning regimen (cytotoxic agents or irradiation) to the thyroid gland.36 It may also be the result of an induced autoimmune reaction against the recipient’s thyroid tissue. In allogeneic transplanted patients, autoimmune thyroid disease has been published in case reports as Graves disease developing after HSCT with concomitant disease of the donor.37 In these cases Graves disease was interpreted as adoptively transferred.22,37 However, de novo Graves disease after allogeneic HSCT from a donor not suffering from Graves disease has also been published.38 More often autoimmune thyroiditis is recognized after allogeneic HSCT.39 In a case report40, Hashimoto’s thyroiditis was diagnosed in a recipient of allogeneic peripheral-blood stem cells (PBSCs) with a positively CD34-selected graft. The donor suffered from hypothyroidism, indicating that autoimmune thyroiditis was most likely transferred by CD34þselected allogeneic PBSC transplantation, and that transfer of autoimmunity cannot be prevented by reducing the number of transplanted lymphocytes. In a prospective study concerning thyroid function after autologous HSCT, four out of 111 patients developed thyroid antibodies, two of whom experienced hypothyroidism.36 Autoimmune cytopenia after HSCT Cytopenia occurring after HSCT may have several causes. Pre-existing alloimmunity e especially in the case of transplantation with an ABO-incompatible graft or the existence of alloantibodies e induced after multiple blood transfusions can cause a mostly transient anaemia after HSCT. Alloantibodies may also react against thrombocytes or granulocytes, causing cytopenia. Besides alloimmune mechanisms, infection can be

Autoimmunity following HSCT 355

responsible for cytopenia after HSCT, in particular of the herpes virus family.41 Cytopenia can be induced by immunosuppression or by antiviral therapy. It is important to distinguish autoimmune cytopenia from these other causes. Autoimmune cytopenia after HSCT is reported as autoimmune haemolytic anaemia (AIHA), idiopathic thrombocytopenia (ITP), granulocytopenia, or a combination of the three.42 Autoimmune cytopenia independent of the stem-cell source (peripheral blood or bone marrow) and of T-cell-depletion procedures of the graft is reported in allogeneic and autologous transplanted patients. In a series of 236 patients who received an allogeneic T-cell-depleted bone-marrow transplantation (BMT) for malignant disease, seven patients were identified with AIHA in a median of 10 (7e25) months after BMT. Response to treatment was poor, with most patients failing steroid therapy.43 Chen et al reported an incidence of AIHA in 3.1 % of patients who underwent allogeneic BMT.44 According to these series AIHA is an important complication of HSCT, with a significant combined mortality in both studies of 50 %. Homeostatic expansion of autoreactive lymphocyte clones may be one cause of post-HSCT AIHA. An additional mechanism leading to AIHA could be loss of control of autoreactive pre-existing clones by a reduced number of Treg cells after conditioning for HSCT. CD4þCD25þ positive Treg cells have been shown to be important in control of haemolysis in the mouse model of AIHA.45 Whether Tregs are reduced after HSCT in patients with AIHA has not been shown so far. A more recent case series of four patients suggests efficacy of rituximab e a chimeric, B-cell-depleting antibody against CD20 e in AIHA or ITP occurring after allogeneic HSCT with reduced-intensity conditioning.46 Thrombocytopenia with a normal or elevated megakaryocyte count in the bone marrow and/or positive anti-platelet antibody titres in peripheral blood occurs after autologous, syngeneic or allogeneic HSCT, irrespective of the stem-cell source.47e50 Several authors have reported on multilineage autoimmune cytopenia or on multiple combined autoimmune phenomena in patients after HSCT. Fatal autoimmune pancytopenia after allogeneic HSCT for aplastic anaemia has been reported. Ten months after BMT the patient developed AIHA and ITP refractory to conventional immunosuppressive therapy. In addition, a granulocyte-specific antibody was detected 4 months later in the same patient.42 Another case report describes a 36-year-old patient with myelodysplasia type RAEB-T who received autologous BMT in first remission of her disease. She had skin eruptions, judged by the authors as ‘autologous GvHD’, resolving under steroids. Thereafter she remained in remission of the MDS. Two years after BMT she developed autoimmune thyroiditis associated with antithyroglobulin and antimicrosomal autoantibodies. Nine months later autoimmune thrombocytopenia developed. Another 14 months later autoimmune haemolytic anaemia caused by warm autoantibodies was diagnosed. In addition, 2 years later the lupus anticoagulant was detected.51 These autoimmune phenomena could be controlled in this patient using immunosuppressive therapy. Not all cases of acquired autoimmune cytopenia after HSCT require immunosuppressive therapy. Self-limiting disease has been reported in a third patient who received autologous BMT for multiple myeloma. She developed autoimmune thyroiditis, ITP, and a positive ANA titre 1 month after BMT. Symptoms and autoantibody titres resolved within 2 months after HSCT.52 In this case, in contrast to the previously described cases, autoimmunity occurred soon after BMT and resolved rapidly without treatment, suggesting a different underlying mechanism. It is quite possible that the control of pre-existing autoreactive T-cell clones in this patient could

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not be maintained after conditioning for BMT through an imbalance of activating and inhibiting factors during immune reconstitution. Myasthenia gravis after HSCT There have been several reports in the literature of patients developing myasthenia gravis after HSCT. There is a strong association with chronic GvHD in these patients.53 Most of the patients developing myasthenia gravis after HSCT were transplanted for aplastic anaemia, a disease which is known to be associated with thymoma.54 However, a high percentage of patients (up to 20 %) are reported to develop autoantibodies to the acetylcholine receptor after BMT, and of these only a minority show symptoms of active myasthenia gravis.55 LATE ALTERED IMMUNITY IN PATIENTS AFTER ALLOGENEIC HSCT The host’s immune system is irrevocably altered through the transfer of the donor immune system after allogeneic HSCT. This may be associated with GvHD, although up to 50% of recipients never experience symptoms of chronic GvHD.56 It is therefore likely that the altered immune system in these patients is associated with immune phenomena other than GvHD. Non-homogeneous repopulation of donor cells or skewed immuno-senescence might contribute to some of the late effects. An as yet poorly defined ‘altered immunity syndrome’ e occurring in long-term survivors of HSCT and not necessarily associated with GvHD e has been described.18 ‘Altered immunity’ in this setting has been proposed to be a syndrome consisting of clinical symptoms such as arthralgia, SICCA syndrome and fatigue in association with the presence of antinuclear antibodies. A prospective evaluation of this concept is still lacking, and in fact we know very little concerning the late effects of allogeneic HSCT on the immune system of the recipient. SUMMARY Due to improved supportive care and less toxic conditioning regimens, patients receiving HSCT are living longer, and the emergence of ‘altered immune’ states is being increasingly recognized. As with any form of profound lymphopenia, autoimmunity occurring during the vigorous phase of homeostatic expansion is often associated with preferential expansion of auto-reacting effector memory T-cells, considered to be due to a failure e often temporary e of the regulatory T-cell system. This probably explains why most autoimmune diseases emerging in this setting are epitope-specific (e.g. thyroid disease and cytopenias), whereas multisystem autoimmune disease such as rheumatoid arthritis is rare. With allogeneic HSCT, adoptive transfer of autoimmune disease has been shown, and the similarities between some infections occurring in HSCT and the manifestations of chronic GvHD complicate the picture. With the growing use of reduced-intensity allogeneic HSCT in an older target population, it is likely that altered immune states will become more of a clinical issue, and prospective data banks concerning both donor and host graft quality with respect to autoimmune disease propensity are important. Although not putative, many

Autoimmunity following HSCT 357

autoantibodies such as antibody to CCP peptide may appear many years before any clinical manifestation, providing a convenient marker of potentially unsuitable donor status. Practice points  graft quality concerning autoimmunity or predisposition for autoimmune diseases should be considered because of the risk of adoptive transferred autoimmunity  epitope-specific autoimmunity can be a cause of thyroid dysfunction or cytopenia after HSCT  infection should always suspected in patients after HSCT as a cause of newly developed rheumatic symptoms

Research agenda  prospective clinical studies are needed to evaluate the incidence and pattern of autoimmune disease after HSCT  possible common pathophysiological mechanisms for GvHD and connectivetissue diseases should be further explored for developing new treatment strategies for GvHD  the long-term and late effects of allogeneic HSCT on the immune system are of interest due to the better outcome of patients after HSCT

CONCLUDING REMARKS After HSCT, the immune system is substantially disturbed. The ensuing immune reconstitution is influenced by multiple factors, many of which are unknown. Intercurrent infection or a genetic predisposition along with unknown events may lead to an ‘altered immunity’ state. A broad range of symptoms and signs are observed, not all of which require therapy. Risk assessment for pre-emptive measures is insufficient due to lacking prospective data. Therefore more data are required concerning the incidence, prognosis and risk factors for autoimmune disease and ‘altered immunity’ after HSCT to enable a logical and effective management of the problem. REFERENCES 1. Gratwohl A, Passweg J, Bocelli-Tyndall C et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplantation 2005; 35: 869e879. 2. Dykewicz CA. Preventing opportunistic infections in bone marrow transplant recipients. Transplant Infectious Disease 1999; 1: 40e49. *3. King C, Ilic A, Koelsch K et al. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 2004; 117: 265e277. 4. Ge Q, Rao VP, Cho BK et al. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/MHC epitopes and strength of their interaction with T cell receptors. Proceedings of the National Academy of Sciences of the USA 2001; 98: 1728e1733.

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