- Email: [email protected]
GRAFT REJECTION AND GRAFT-VERSUS-HOST DISEASE: MIRROR IMAGES
1468
increase is
calcium-dependent and is abrogated by cyclo-oxygenase inhibitors. 10 A similar mechanism has been postulated to explain the flares of psoriasis observed after administration of beta-adrenergic i blockers. 9,11
Some researchers regard psoriasis as a chronic inflammatory disorder mediated by immune cells. 12 Interferons activate various leucocyte functions 13 and participate in regulating the production of other cytokines.14 Although the role of these cytokines in psoriasis is unknown, lithium carbonate, another agent shown to exacerbate or induce psoriasis, may produce these changes via redistribution and activation of epidermal leucocytes. Furthermore, keratinocytes have been reported to perform some macrophage-like functions, including production and release of interleukin-L 15 Conceivably, interferon, a known activator of macrophage functions,13 may precipitate inflammatory events by direct stimulation of
keratinocytes. The observed benefits of the retinoic-acid derivatives
(etretinate and 13-cis-retinoic acid) in psoriasis16 may be related to antagonism to IFNa. Retinoic acid blocks IFNa’s antiviral effect and inhibits its production at the transcriptional level. 17 The clinical course of psoriasis in cancer patients has been found to vary according to the activity of the malignant condition. Schadijew and Kalamkaryan 18 noted improvement of psoriasis with progression of the malignancy and exacerbation of the skin disorder with remission or extirpation of the tumour. We observed objective improvement of the metastatic lesions in two of our patients; whether the exacerbation of the psoriasis related to this is unknown. We that further studies of the suggest pathophysiology of psoriasis should include a close examination of the interferon system in the epidermis. was
We thank Linda Reckeweg for her assistance in the preparation of this manuscript. This work was supported in part by a grant from Hoffmann LaRoche Laboratories, Nutley, New Jersey.
Correspondence should be addressed to J.
R.
Q.
REFERENCES
Quesada JR, Swanson DA, Trindade A, Gutterman JU. Renal cell carcinoma: Antitumor effects of leukocyte interferon. Cancer Res 1983; 43: 940-47. 2. Quesada JR, Rios A, Swanson DA, Gutterman JU. Phase II study of recombinant DNA-derived alpha interferon in renal cell carcinoma. J Clin Oncol 1985; 3: 1086. 3. Yaar M, Karassik RL, Schnipper LE, Gilchrest BA. Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol 1985; 85: 1.
70-74. 4. Gutterman
JU, Fine S, Quesada JR. Recombinant leukocyte A interferon: Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med 1982; 96: 549-56. 5. Skoven S, Thorman J. Lithium compound treatment and psoriasis. Arch
Hypothesis GRAFT
REJECTION AND GRAFT-VERSUS-HOST DISEASE: MIRROR IMAGES
ROBERT PETER GALE
YAIR REISNER
Department of Medicine, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California 90024, USA; and Department of Biophysics, Weizmann Institute of Science, Rehovot 76100, Israel Graft rejection and graft-versus-host disease (GvHD) complicate bone marrow transin animals and man. The likelihood of each plantation correlates with the degree of genetic disparity between donor and recipient. However, instead of a direct relation between graft rejection and GvHD, these events are inversely correlated: in most instances, they are mutually exclusive. A similar, complex relation exists with a third possible event,
Summary
graft-versus-leukaemia. Attempts to suppress graft rejection or GvHD are likely to increase the reciprocal outcomes unless additional
measures are
instituted.
INTRODUCTION
BONE marrow transplantation is increasingly used in man.’ In genetically identical twins there are no immunological barriers to bone marrow transplantation, but in other circumstances general disparities result in immune-related complications including graft rejection and graft-versus-host disease (GvHD). Graft rejection and GvHD are complex events. Experimental and clinical evidence suggests that both are mediated primarily by T lymphocytes:2-7 T lymphocytes responsible for graft rejection are derived from the recipient; T lymphocytes responsible for GvHD are introduced into the recipient by the donor bone marrow inoculum. Extensive studies of graft rejection and GvHD have been reported.
Analysis of graft rejection is hampered by experimental difficulties. The need is for specific in-vivo modulation of T cells in the recipient, and this must be achieved without complication of the analysis by death from GvHD. Few studies meet these requirements. In GvHD, the role of T lymphocytes is more easily defined since the cells can be manipulated in vitro before transplantation. The experimental conditions must exclude graft rejection; this is usually accomplished by immunosuppression of the recipient or by use of genetically restricted animals.
Dermatol 1979; 115: 1185-87. 6. 7
Bjerke JR, Livden JK, Degree M, Matre R: Interferon in suction blister fluid from psoriatic lesions. Br J Dermatol 1983; 108: 295-99. Bjerke JR, Haukenes G, Livden JK, et al. Activated T lymphocytes, interferon and retrovirus-like particles in psoriatic lesions. Arch Dermatol 1983; 119:
955-56. 8. Diezel W, Saschke SR, Sonnichsen N. Detection of interferon in the sera of patients with psoriasis and its enhancement by PUVA treatment. Br J Dermatol 1983; 109: 549-52. 9. Voorhees JJ, Marcelo CL, Duell EA: Cyclic AMP, cyclic GMP and glucocorticoids as potential metabolic regulators of epidermal proliferation and differentiation. J Invest Dermatol 1975, 65: 179-80. 10. Tovey MG. Interferon and cyclic nucleotides. In: Gresser I, ed. Interferon. London: Academic Press, 1982: 23-42. 11. Felix RH, Ive EA, Dahl MGC. Cutaneous and ocular reactions to practolol. Br
Med J 1974; iv:
12. Bos 13.
JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH. Immunocompetent cells in psoriasis. Arch Dermatol Res 1983; 275: 181-89. DeMaeyer-Guignard J, DeMaeyer E. Immunomodulation by interferons. Recent developments. In: Gresser I, ed. Interferon 6. London: Academic Press, 1985: 69-92. VR, Rouse BT, Moore RN. Regulation of interleukin
14. Candler
1 production by alpha and beta interferons: Evidence for both direct and indirect enhancement. J Interferon Res 1985; 5: 179-89. 15. Luger TA, Sztein MB, Schmidt JA, et al. Properties of murine and human epidermal cell derived thymocyte-activating factor. Fed Proc 1983, 42:
2772-76. 16.
321-24. 17.
18.
Kaplan RP, Russell DH, Lowe NJ. Etrinate therapy for psoriasis. clinical responses, remission times, epidermal DNA and polyamine responses. Am Acad Dermatol 1983; 8: 95-102. Blalock EJ, Gifford GE. Retinoic acid induced transcriptional control of interferon production. Proc Natl Acad Sci USA 1977; 74: 5382-86 Schadijew HK, Kalamkaryan AA. The course of psoriasis in cancer patients. Br J Dermatol 1983; 109: 365.
1469 with
GvHD; graft
important determinant of graft rejection and extent of genetic disparity between donor and In general, genetic disparity correlates with recipient.
rejection. Graft failure
antigenic disparity. Clearly not all gene products antigenic; some are not immunogenic whereas others
In the model we present, the same individuals are at highest risk for graft rejection and GvHD. Thus, if one could prevent graft rejection in an individual at high risk by more intense pretransplant immunosuppression, that individual would be at substantial risk of GvHD. Clearly GvHD cannot occur unless graft rejection is prevented, since they are mutually exclusive. This hypothetical relation is supported by data from bone marrow transplants in patients with leukaemia. In more than 2000 patients who received HLA-identical bone marrow transplants during the past decade, graft rejection was rare (< 1 %) while substantial GvHD ( grade 2) occurred in approximately 45% of individuals at high risk.I,9 One probable reason for the dominance of GvHD over graft rejection in this cohort is the abundance ofT cells present in the bone marrow inoculum compared with the recipient marrow depleted by pretransplant chemotherapy and radiation. 10 Experimental data in primates suggest a 2 to 3 log excess of donor-versus-recipient T cells. It is also likely that attempts to prevent graft rejection have been more successful than those to prevent GvHD. Data in about 400 patients with leukaemia receiving HLA-identical, T-cell-depleted bone marrow transplants indicate that whereas the incidence and severity of GvHD is reduced from 45% to 15% there is a significant increase in graft rejection from 1% to 15 % .l Recent data suggest an even higher incidence of graft rejection following HLA-mismatched T-cell-depleted marrow." Thus, pretransplant reduction of T cells in the bone marrow causes a swing from GvHD to graft rejection. Experimental data in primates suggest comparable numbers of residual recipient and donor T cells in the bone marrow inoculum when T cells are depleted in vitro.1O In patients with little or no genetic disparity, both reactions may be comparably weak, may neutralise one another, or may be clinically undetectable. A similar inverse relation probably exists between graft rejection and GvHD in transplants for aplastic anaemia. Individuals with aplastic anaemia usually have a normal immune system. Furthermore, these patients receive less intense pretransplant immunosuppression than those with leukaemia. As a consequence, host residual immunocompetence is greater than in patients with leukaemia, resulting in a substantially higher incidence of graft rejection. Few patients with aplastic anaemia have received depleted bone marrow transplants, since the T-cell depletion would be expected to enhance the risk of graft rejection; preliminary data indicate a 50% risk.
The
most
GvHD is the
are are
inaccessible to the immune system. Other related or unrelated genes may regulate immune responses to an antigen. Nevertheless, the sum of these immunogenic disparities is correlated with the extent of genetic mismatching between donor and recipient and subsequently with the likelihood of graft rejection and GvHD (figure, A). Disparity for antigens encoded by the major histocompatibility complex is associated with a substantial increase in the likelihood of graft rejection and GvHD. The likelihood of graft rejection is about 1% in recipients ofHLAidentical transplants versus 15% in recipients of HLAmismatched grafts and, similarly, the degree of HLA mismatching is correlated with the actuarial probability of acute GvHD.8 In mice that are identical at the major histocompatibility complex, progressive increments in the degree of minor antigen disparities increase the likelihood of graft rejection and GvHD; similar data are not available in outbred species such as man because minor loci are difficult to identify and quantitate. REJECTION VERSUS GvHD
If both graft rejection and GvHD are directly correlated with increasing genetic disparity, they might be expected to correlate with one another-eg, individuals most likely to reject their graft are those most likely to get GvHD-as in the’ figure, B. In fact, however, we see an inverse relation between graft rejection and GvHD, indicated schematically in the figure, C. The reason for this is that graft rejection and GvHD tend to be mutually exclusive: individuals who reject the graft cannot have GvHD, and individuals with GvHD cannot reject the graft. There are rare exceptions to these concepts-for example, late graft failure in an individual with GvHD. It is important to differentiate graft failure from
rejection implies
an
can occur
immunological
severe
mechanism of
graft
failure.
GRAFT VERSUS LEUKAEMIA
Bone marrow transplantation has a third immunological aspect-graft versus leukaemia. Considerable data in animals and man indicate that transplantation of genetically disparate
Relations between rejection, GvHD, and GvL.
cells is associated with an antileukaemic effect referred to as GvL.’3 In some experimental systems it is possible to distinguish between GvHD and GvL.14 In man this distinction is not yet achievable and we do not know whether leukaemia-specific antigens exist. The recent use of T-celldepleted bone marrow may answer this question by indicating whether leukaemia is more likely to relapse when GvHD is reduced or eliminated. Many of the arguments that we raise in the context of graft rejection and GvHD are relevant to GvL. The chance of a GvL effect is likely to be correlated with the degree of antigenic disparity between normal cells of the donor and leukaemia cells of the recipient.
1470
If recipient leukaemia cells display all the histocompatibility antigens present on their normal counterparts, one would predict a direct correlation between GvHD and GvL. If leukaemia-specific antigens exist (for which there are no convincing data), GvHD or GvL may be distinguishable and may not correlate precisely. A key question in this context is whether prevention of GvHD by the use of T-cell-depleted marrow will also abolish GvL. In such patients, donor type T cells are generally tolerant of host histocompatibility antigens; it is not known whether similar tolerance will extend to leukaemia-specific antigens or against normal determinants that might be present on malignant cells. Since GvL cannot be measured directly, one can only indirectly assess its intensity as an inverse correlate of the probability of leukaemia relapse. The possible relations between graft rejection, GvHD, and GvL can be considered as follows. If graft rejection occurs, it is usually fatal within a short time; consequently, these patients are not at extended risk for leukaemia relapse. Similarly, patients who contract severe GvHD usually die rapidly and are likewise not at prolonged risk for leukaemia relapse. It is possible to correct partly for this decreased interval at risk by calculating actuarial rather than actual relapsed rates, by the product moment method of Kaplan and Meier. This technique, although useful, is not entirely appropriate, since it assumes competing but unrelated causes of treatment failure, whereas GvHD and GvL may be related. Part D of the figure schematically indicates these complex relations between graft rejection, GvHD, and GvL as observed clinically. IMPLICATIONS OF THE HYPOTHESIS
If the relations indicated in part D of the figure are correct, interventions designed to decrease the likelihood of GvHD (incidence, severity, or both) are projected to result in an increased risk of graft rejection and of leukaemia relapse. There is already a considerable body of data concerning graft rejection and GvHD in animals and man to suggest that this prediction is correct (reviewed in refs 11and 12). Data with regard to leukaemia relapse are controversial. Data regarding a possible antileukaemia effect of GvHD in AML in first remission are controversial. Similarly, it is uncertain ifT-cell depletion increases the likelihood of leukaemia relapse. Preliminary data in chronic myelogenous leukaemia, chronic phase, suggest an increased risk of relapse in recipients of T-cell-depleted grafts in some but not all studies (Gale. RP, Goldman JM, Champlin RE, Unpublished). On the basis of this model we also predict that attempts to modify GvHD may result in an increased likelihood of leukaemia relapse. Data in animals support this hypothesis in
all, cases. Preliminary data in man are Part of the reason for these disparities may be contradictory. that in some instances GvHD and GvL are mediated via GvHD whereas in others they are distinct. Another possibility is that the efficacy of the conditioning regimen or the remission status of the patient will influence the likelihood of leukaemia relapse. In one study, a pretransplant conditioning regimen that was very effective in eradicating leukaemia in allogeneic transplant recipients was associated with a high relapse rate in genetically identical twins.l5 One possible explanation was that the more effective regimen achieves its advantage by increasing GvHD rather than by greater direct antileukaemia activity. Another was that leukaemia recurrence in twins may reflect the de novo induction of leukaemia in donor cells. some, but not
There are several possible ways of interpreting the relations between graft rejection, GvHD, and GvL. In our model we depict these outcomes with identical slopes. This notion may not be correct; sensitivity of the host to different outcomes may differ. The quantitative relation between T cells and each event might also vary. For example, even if an identical T-cell subpopulation caused GvHD and GvL, it might require 10 times more cells to produce the former; were this true, 90% reduction in T cells would greatly decrease GvHD without affecting GvL. Our model should not be interpreted to indicate that prevention of GvHD will invariably lead to increased graft rejection or leukaemia relapse. Additional measures, such as increased pre-transplant or post-transplant immunosuppression or more effective antileukaemia therapy may prevent these adverse outcomes. Preliminary data indicate that these approaches may be successful. Celene Ushry, Dvora Ochert, and Gwen Dangerfield provided secretarial assistance. The work was supported in part by grant CA 23175 from the National Cancer Institute, United States Public Health Service. REFERENCES
RP, ed. Recent advances in bone marrow transplantation. New York: Alan R Liss, 1984: 1-905. 2. Grebe SC, Streilein JW. Graft-versus-host reactions a review. Adv Immunol 1976, 22: 119-221. 3. Seemayer TA. The graft-versus-host reaction- a pathogenetic mechanism of experimental and human disease. Perspect Pediatr Pathol 1979, 5: 93-136 4 van Bekkum DW Graft-versus-host disease. In: van Bekkum DW, Lowenberg B, eds Bone marrow transplantation, biological mechanisms and clinical practice. New York Dekker, 1985, 147-212 5. Graft-versus-host reaction Immunol Rev 1986; 88: 1-238 6. Elkins WL Cellular immunology and the pathogenesis of graft-versus-host reactions Prog Allergy 1971, 15: 78-187. 7 Vriesendorp HM Engraftment of hemopoietic cells In: van Bekkum DW, Löwenberg B, eds. Bone marrow transplantation, biological mechanisms and clinical practice. New York Dekker, 1985; 73-145 8. Beatty PG, Clift RA, Mickelson EM, et al. Marrow transplantation from related donors other than HLA-identical siblings N Engl J Med 1985; 313: 765-71 9. Gale RP, Bortin MM, van Bekkum DW, et al. Acute graft-vs-host disease following bone marrow transplantation in humans assessment of risk factors. Unpublished 10. Reisner Y, Ben-Bassat I, Douer D, et al Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation. Proc Natl Acad Sci (in 1. Gale
press). 11. Gale RP. T
cells, bone marrow transplantation and immunotherapy. In- Fahey JL (moderator), Immune aspects of disease. Ann Intern Med (in press). 12. Franceschini F, Butturini A, Gale RP. Clinical trials of T-cell depletion. In: Gale RP, Champlin RE, eds. Recent advances in bone marrow transplantation. New York: Alan R. Liss (in press). 13. Okunewick JP, Meredith RF, eds. Graft-versus-leukemia in man and animal models. Boca Raton, Florida: CRC Press, 1981. 14. Bortin MM, Truitt RL, Rimm AA, Bach FH. Graft versus leukemia reactivity induced by alloimmunization without augmentation of graft versus host reactivity. Nature 1979; 281: 490-91. GW, Tutschka PJ, Brookmeyer R,
15. Santos
et
nonlymphocytic leukemia after treatment N Engl J Med 1983, 309: 1347-53
al. Marrow transplantation for acute with busulfan and cyclophosphamide
"What brings patients to doctors is discomfort and dysfunction, not the pathology which may underlie them. It matters—and matters greatly—to strategies for cure just how far bodily malfunction is causing problems in living and how far the symptoms are the somatic embodiment of problems in living; rarely are they simply one or the other. The doctor’s task is to identify their sources when this can be done, to reach agreement with the patient about their significance, to indicate the range of available remedies, and to assist the patient in coping with what is beyond repair. In this process, biomedical knowledge is necessary but not sufficient; the doctor’s transactions with the patient must be informed by the social sciences. Neither brainlessness nor mindlessness can be tolerated in psychiatry or medicine. The unique role of psychiatry in medicine will be found in the extent to which it contributes to the of and understanding psychosomatic somatopsychic integration ..."—LEON EISENBERG.—Mindlessness and brainlessness in psychiatry. Br J Psychiatry 1986; 148: 497-508.
increase is
calcium-dependent and is abrogated by cyclo-oxygenase inhibitors. 10 A similar mechanism has been postulated to explain the flares of psoriasis observed after administration of beta-adrenergic i blockers. 9,11
Some researchers regard psoriasis as a chronic inflammatory disorder mediated by immune cells. 12 Interferons activate various leucocyte functions 13 and participate in regulating the production of other cytokines.14 Although the role of these cytokines in psoriasis is unknown, lithium carbonate, another agent shown to exacerbate or induce psoriasis, may produce these changes via redistribution and activation of epidermal leucocytes. Furthermore, keratinocytes have been reported to perform some macrophage-like functions, including production and release of interleukin-L 15 Conceivably, interferon, a known activator of macrophage functions,13 may precipitate inflammatory events by direct stimulation of
keratinocytes. The observed benefits of the retinoic-acid derivatives
(etretinate and 13-cis-retinoic acid) in psoriasis16 may be related to antagonism to IFNa. Retinoic acid blocks IFNa’s antiviral effect and inhibits its production at the transcriptional level. 17 The clinical course of psoriasis in cancer patients has been found to vary according to the activity of the malignant condition. Schadijew and Kalamkaryan 18 noted improvement of psoriasis with progression of the malignancy and exacerbation of the skin disorder with remission or extirpation of the tumour. We observed objective improvement of the metastatic lesions in two of our patients; whether the exacerbation of the psoriasis related to this is unknown. We that further studies of the suggest pathophysiology of psoriasis should include a close examination of the interferon system in the epidermis. was
We thank Linda Reckeweg for her assistance in the preparation of this manuscript. This work was supported in part by a grant from Hoffmann LaRoche Laboratories, Nutley, New Jersey.
Correspondence should be addressed to J.
R.
Q.
REFERENCES
Quesada JR, Swanson DA, Trindade A, Gutterman JU. Renal cell carcinoma: Antitumor effects of leukocyte interferon. Cancer Res 1983; 43: 940-47. 2. Quesada JR, Rios A, Swanson DA, Gutterman JU. Phase II study of recombinant DNA-derived alpha interferon in renal cell carcinoma. J Clin Oncol 1985; 3: 1086. 3. Yaar M, Karassik RL, Schnipper LE, Gilchrest BA. Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol 1985; 85: 1.
70-74. 4. Gutterman
JU, Fine S, Quesada JR. Recombinant leukocyte A interferon: Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med 1982; 96: 549-56. 5. Skoven S, Thorman J. Lithium compound treatment and psoriasis. Arch
Hypothesis GRAFT
REJECTION AND GRAFT-VERSUS-HOST DISEASE: MIRROR IMAGES
ROBERT PETER GALE
YAIR REISNER
Department of Medicine, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California 90024, USA; and Department of Biophysics, Weizmann Institute of Science, Rehovot 76100, Israel Graft rejection and graft-versus-host disease (GvHD) complicate bone marrow transin animals and man. The likelihood of each plantation correlates with the degree of genetic disparity between donor and recipient. However, instead of a direct relation between graft rejection and GvHD, these events are inversely correlated: in most instances, they are mutually exclusive. A similar, complex relation exists with a third possible event,
Summary
graft-versus-leukaemia. Attempts to suppress graft rejection or GvHD are likely to increase the reciprocal outcomes unless additional
measures are
instituted.
INTRODUCTION
BONE marrow transplantation is increasingly used in man.’ In genetically identical twins there are no immunological barriers to bone marrow transplantation, but in other circumstances general disparities result in immune-related complications including graft rejection and graft-versus-host disease (GvHD). Graft rejection and GvHD are complex events. Experimental and clinical evidence suggests that both are mediated primarily by T lymphocytes:2-7 T lymphocytes responsible for graft rejection are derived from the recipient; T lymphocytes responsible for GvHD are introduced into the recipient by the donor bone marrow inoculum. Extensive studies of graft rejection and GvHD have been reported.
Analysis of graft rejection is hampered by experimental difficulties. The need is for specific in-vivo modulation of T cells in the recipient, and this must be achieved without complication of the analysis by death from GvHD. Few studies meet these requirements. In GvHD, the role of T lymphocytes is more easily defined since the cells can be manipulated in vitro before transplantation. The experimental conditions must exclude graft rejection; this is usually accomplished by immunosuppression of the recipient or by use of genetically restricted animals.
Dermatol 1979; 115: 1185-87. 6. 7
Bjerke JR, Livden JK, Degree M, Matre R: Interferon in suction blister fluid from psoriatic lesions. Br J Dermatol 1983; 108: 295-99. Bjerke JR, Haukenes G, Livden JK, et al. Activated T lymphocytes, interferon and retrovirus-like particles in psoriatic lesions. Arch Dermatol 1983; 119:
955-56. 8. Diezel W, Saschke SR, Sonnichsen N. Detection of interferon in the sera of patients with psoriasis and its enhancement by PUVA treatment. Br J Dermatol 1983; 109: 549-52. 9. Voorhees JJ, Marcelo CL, Duell EA: Cyclic AMP, cyclic GMP and glucocorticoids as potential metabolic regulators of epidermal proliferation and differentiation. J Invest Dermatol 1975, 65: 179-80. 10. Tovey MG. Interferon and cyclic nucleotides. In: Gresser I, ed. Interferon. London: Academic Press, 1982: 23-42. 11. Felix RH, Ive EA, Dahl MGC. Cutaneous and ocular reactions to practolol. Br
Med J 1974; iv:
12. Bos 13.
JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH. Immunocompetent cells in psoriasis. Arch Dermatol Res 1983; 275: 181-89. DeMaeyer-Guignard J, DeMaeyer E. Immunomodulation by interferons. Recent developments. In: Gresser I, ed. Interferon 6. London: Academic Press, 1985: 69-92. VR, Rouse BT, Moore RN. Regulation of interleukin
14. Candler
1 production by alpha and beta interferons: Evidence for both direct and indirect enhancement. J Interferon Res 1985; 5: 179-89. 15. Luger TA, Sztein MB, Schmidt JA, et al. Properties of murine and human epidermal cell derived thymocyte-activating factor. Fed Proc 1983, 42:
2772-76. 16.
321-24. 17.
18.
Kaplan RP, Russell DH, Lowe NJ. Etrinate therapy for psoriasis. clinical responses, remission times, epidermal DNA and polyamine responses. Am Acad Dermatol 1983; 8: 95-102. Blalock EJ, Gifford GE. Retinoic acid induced transcriptional control of interferon production. Proc Natl Acad Sci USA 1977; 74: 5382-86 Schadijew HK, Kalamkaryan AA. The course of psoriasis in cancer patients. Br J Dermatol 1983; 109: 365.
1469 with
GvHD; graft
important determinant of graft rejection and extent of genetic disparity between donor and In general, genetic disparity correlates with recipient.
rejection. Graft failure
antigenic disparity. Clearly not all gene products antigenic; some are not immunogenic whereas others
In the model we present, the same individuals are at highest risk for graft rejection and GvHD. Thus, if one could prevent graft rejection in an individual at high risk by more intense pretransplant immunosuppression, that individual would be at substantial risk of GvHD. Clearly GvHD cannot occur unless graft rejection is prevented, since they are mutually exclusive. This hypothetical relation is supported by data from bone marrow transplants in patients with leukaemia. In more than 2000 patients who received HLA-identical bone marrow transplants during the past decade, graft rejection was rare (< 1 %) while substantial GvHD ( grade 2) occurred in approximately 45% of individuals at high risk.I,9 One probable reason for the dominance of GvHD over graft rejection in this cohort is the abundance ofT cells present in the bone marrow inoculum compared with the recipient marrow depleted by pretransplant chemotherapy and radiation. 10 Experimental data in primates suggest a 2 to 3 log excess of donor-versus-recipient T cells. It is also likely that attempts to prevent graft rejection have been more successful than those to prevent GvHD. Data in about 400 patients with leukaemia receiving HLA-identical, T-cell-depleted bone marrow transplants indicate that whereas the incidence and severity of GvHD is reduced from 45% to 15% there is a significant increase in graft rejection from 1% to 15 % .l Recent data suggest an even higher incidence of graft rejection following HLA-mismatched T-cell-depleted marrow." Thus, pretransplant reduction of T cells in the bone marrow causes a swing from GvHD to graft rejection. Experimental data in primates suggest comparable numbers of residual recipient and donor T cells in the bone marrow inoculum when T cells are depleted in vitro.1O In patients with little or no genetic disparity, both reactions may be comparably weak, may neutralise one another, or may be clinically undetectable. A similar inverse relation probably exists between graft rejection and GvHD in transplants for aplastic anaemia. Individuals with aplastic anaemia usually have a normal immune system. Furthermore, these patients receive less intense pretransplant immunosuppression than those with leukaemia. As a consequence, host residual immunocompetence is greater than in patients with leukaemia, resulting in a substantially higher incidence of graft rejection. Few patients with aplastic anaemia have received depleted bone marrow transplants, since the T-cell depletion would be expected to enhance the risk of graft rejection; preliminary data indicate a 50% risk.
The
most
GvHD is the
are are
inaccessible to the immune system. Other related or unrelated genes may regulate immune responses to an antigen. Nevertheless, the sum of these immunogenic disparities is correlated with the extent of genetic mismatching between donor and recipient and subsequently with the likelihood of graft rejection and GvHD (figure, A). Disparity for antigens encoded by the major histocompatibility complex is associated with a substantial increase in the likelihood of graft rejection and GvHD. The likelihood of graft rejection is about 1% in recipients ofHLAidentical transplants versus 15% in recipients of HLAmismatched grafts and, similarly, the degree of HLA mismatching is correlated with the actuarial probability of acute GvHD.8 In mice that are identical at the major histocompatibility complex, progressive increments in the degree of minor antigen disparities increase the likelihood of graft rejection and GvHD; similar data are not available in outbred species such as man because minor loci are difficult to identify and quantitate. REJECTION VERSUS GvHD
If both graft rejection and GvHD are directly correlated with increasing genetic disparity, they might be expected to correlate with one another-eg, individuals most likely to reject their graft are those most likely to get GvHD-as in the’ figure, B. In fact, however, we see an inverse relation between graft rejection and GvHD, indicated schematically in the figure, C. The reason for this is that graft rejection and GvHD tend to be mutually exclusive: individuals who reject the graft cannot have GvHD, and individuals with GvHD cannot reject the graft. There are rare exceptions to these concepts-for example, late graft failure in an individual with GvHD. It is important to differentiate graft failure from
rejection implies
an
can occur
immunological
severe
mechanism of
graft
failure.
GRAFT VERSUS LEUKAEMIA
Bone marrow transplantation has a third immunological aspect-graft versus leukaemia. Considerable data in animals and man indicate that transplantation of genetically disparate
Relations between rejection, GvHD, and GvL.
cells is associated with an antileukaemic effect referred to as GvL.’3 In some experimental systems it is possible to distinguish between GvHD and GvL.14 In man this distinction is not yet achievable and we do not know whether leukaemia-specific antigens exist. The recent use of T-celldepleted bone marrow may answer this question by indicating whether leukaemia is more likely to relapse when GvHD is reduced or eliminated. Many of the arguments that we raise in the context of graft rejection and GvHD are relevant to GvL. The chance of a GvL effect is likely to be correlated with the degree of antigenic disparity between normal cells of the donor and leukaemia cells of the recipient.
1470
If recipient leukaemia cells display all the histocompatibility antigens present on their normal counterparts, one would predict a direct correlation between GvHD and GvL. If leukaemia-specific antigens exist (for which there are no convincing data), GvHD or GvL may be distinguishable and may not correlate precisely. A key question in this context is whether prevention of GvHD by the use of T-cell-depleted marrow will also abolish GvL. In such patients, donor type T cells are generally tolerant of host histocompatibility antigens; it is not known whether similar tolerance will extend to leukaemia-specific antigens or against normal determinants that might be present on malignant cells. Since GvL cannot be measured directly, one can only indirectly assess its intensity as an inverse correlate of the probability of leukaemia relapse. The possible relations between graft rejection, GvHD, and GvL can be considered as follows. If graft rejection occurs, it is usually fatal within a short time; consequently, these patients are not at extended risk for leukaemia relapse. Similarly, patients who contract severe GvHD usually die rapidly and are likewise not at prolonged risk for leukaemia relapse. It is possible to correct partly for this decreased interval at risk by calculating actuarial rather than actual relapsed rates, by the product moment method of Kaplan and Meier. This technique, although useful, is not entirely appropriate, since it assumes competing but unrelated causes of treatment failure, whereas GvHD and GvL may be related. Part D of the figure schematically indicates these complex relations between graft rejection, GvHD, and GvL as observed clinically. IMPLICATIONS OF THE HYPOTHESIS
If the relations indicated in part D of the figure are correct, interventions designed to decrease the likelihood of GvHD (incidence, severity, or both) are projected to result in an increased risk of graft rejection and of leukaemia relapse. There is already a considerable body of data concerning graft rejection and GvHD in animals and man to suggest that this prediction is correct (reviewed in refs 11and 12). Data with regard to leukaemia relapse are controversial. Data regarding a possible antileukaemia effect of GvHD in AML in first remission are controversial. Similarly, it is uncertain ifT-cell depletion increases the likelihood of leukaemia relapse. Preliminary data in chronic myelogenous leukaemia, chronic phase, suggest an increased risk of relapse in recipients of T-cell-depleted grafts in some but not all studies (Gale. RP, Goldman JM, Champlin RE, Unpublished). On the basis of this model we also predict that attempts to modify GvHD may result in an increased likelihood of leukaemia relapse. Data in animals support this hypothesis in
all, cases. Preliminary data in man are Part of the reason for these disparities may be contradictory. that in some instances GvHD and GvL are mediated via GvHD whereas in others they are distinct. Another possibility is that the efficacy of the conditioning regimen or the remission status of the patient will influence the likelihood of leukaemia relapse. In one study, a pretransplant conditioning regimen that was very effective in eradicating leukaemia in allogeneic transplant recipients was associated with a high relapse rate in genetically identical twins.l5 One possible explanation was that the more effective regimen achieves its advantage by increasing GvHD rather than by greater direct antileukaemia activity. Another was that leukaemia recurrence in twins may reflect the de novo induction of leukaemia in donor cells. some, but not
There are several possible ways of interpreting the relations between graft rejection, GvHD, and GvL. In our model we depict these outcomes with identical slopes. This notion may not be correct; sensitivity of the host to different outcomes may differ. The quantitative relation between T cells and each event might also vary. For example, even if an identical T-cell subpopulation caused GvHD and GvL, it might require 10 times more cells to produce the former; were this true, 90% reduction in T cells would greatly decrease GvHD without affecting GvL. Our model should not be interpreted to indicate that prevention of GvHD will invariably lead to increased graft rejection or leukaemia relapse. Additional measures, such as increased pre-transplant or post-transplant immunosuppression or more effective antileukaemia therapy may prevent these adverse outcomes. Preliminary data indicate that these approaches may be successful. Celene Ushry, Dvora Ochert, and Gwen Dangerfield provided secretarial assistance. The work was supported in part by grant CA 23175 from the National Cancer Institute, United States Public Health Service. REFERENCES
RP, ed. Recent advances in bone marrow transplantation. New York: Alan R Liss, 1984: 1-905. 2. Grebe SC, Streilein JW. Graft-versus-host reactions a review. Adv Immunol 1976, 22: 119-221. 3. Seemayer TA. The graft-versus-host reaction- a pathogenetic mechanism of experimental and human disease. Perspect Pediatr Pathol 1979, 5: 93-136 4 van Bekkum DW Graft-versus-host disease. In: van Bekkum DW, Lowenberg B, eds Bone marrow transplantation, biological mechanisms and clinical practice. New York Dekker, 1985, 147-212 5. Graft-versus-host reaction Immunol Rev 1986; 88: 1-238 6. Elkins WL Cellular immunology and the pathogenesis of graft-versus-host reactions Prog Allergy 1971, 15: 78-187. 7 Vriesendorp HM Engraftment of hemopoietic cells In: van Bekkum DW, Löwenberg B, eds. Bone marrow transplantation, biological mechanisms and clinical practice. New York Dekker, 1985; 73-145 8. Beatty PG, Clift RA, Mickelson EM, et al. Marrow transplantation from related donors other than HLA-identical siblings N Engl J Med 1985; 313: 765-71 9. Gale RP, Bortin MM, van Bekkum DW, et al. Acute graft-vs-host disease following bone marrow transplantation in humans assessment of risk factors. Unpublished 10. Reisner Y, Ben-Bassat I, Douer D, et al Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation. Proc Natl Acad Sci (in 1. Gale
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al. Marrow transplantation for acute with busulfan and cyclophosphamide
"What brings patients to doctors is discomfort and dysfunction, not the pathology which may underlie them. It matters—and matters greatly—to strategies for cure just how far bodily malfunction is causing problems in living and how far the symptoms are the somatic embodiment of problems in living; rarely are they simply one or the other. The doctor’s task is to identify their sources when this can be done, to reach agreement with the patient about their significance, to indicate the range of available remedies, and to assist the patient in coping with what is beyond repair. In this process, biomedical knowledge is necessary but not sufficient; the doctor’s transactions with the patient must be informed by the social sciences. Neither brainlessness nor mindlessness can be tolerated in psychiatry or medicine. The unique role of psychiatry in medicine will be found in the extent to which it contributes to the of and understanding psychosomatic somatopsychic integration ..."—LEON EISENBERG.—Mindlessness and brainlessness in psychiatry. Br J Psychiatry 1986; 148: 497-508.