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| Year : 2005 | Volume
: 16
| Issue : 4 | Page : 498-505 |
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| Transplantation Tolerance |
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Karl L Womer
Renal Division, Department of Medicine, University of Florida College of Medicine, And Malcom Randall VAMC, Gainesville, FL, USA
Click here for correspondence address and email
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How to cite this article:
Womer KL. Transplantation Tolerance. Saudi J Kidney Dis Transpl 2005;16:498-505 |
 Introduction | |  |
Fifty years have passed since the seminal contribution of Billingham, Brent and Medawar in Nature entitled " 'Actively Acquired Tolerance' of Foreign Cells" [1] that paved the way for what is now commonly referred to as transplantation tolerance. Often called the "Holy Grail" of transplant medicine, the phenomenon has been as elusive to researchers, at least in the clinical setting, as it is intriguing. Although the major barriers preventing the translation of experimental tolerance strategies to the clinic remain immunologic in nature, as the concept approaches clinical reality, various safety and ethical concerns become increasingly important. The field of renal transplantation has enjoyed recent dramatic pharmacologicrelated improvements in acute rejection and short-term graft survival rates, [2] which raises the standard for any clinical tolerance trial and has even caused some to question the very need for clinical tolerance.
However, recent registry analysis reveals that long-term graft survival has not improved significantly during the period from 1995-2000, [3] suggesting that the maximal benefit of heightened generalized immunosuppression may have been achieved. Furthermore, immunosuppression is associated with tremendous economic costs, significant toxicities, and continuing problems with noncompliance. Although it remains unproven whether tolerance will solve the problem of late renal allograft loss, [4] these issues have sparked renewed interest in the development of protocols that provide stable, long-term graft survival independent of chronic immunosuppression. [5],[6] This review will provide an overview of the general mechanisms involved in the induction and maintenance of tolerance in the transplant setting and of the current approaches being used to bridge the gap between experimental and clinical studies.
| Definition | | |
Disagreement remains over the most accurate definition of transplantation tolerance. Immunologic non-reactivity to one set of antigens while maintaining reactivity to others is the classic definition of tolerance. Such a definition allows for the antigen specificity important to transplantation tolerance, but fails to distinguish between self-tolerance and donor-specific tolerance. The absence of allograft rejection, a state enjoyed by most recipients of allografts in the current era, also fails as a suitable definition. Generalized immunosuppression in these recipients violates the antigen specificity feature, since these medications suppress immunologic responses not only to allograft antigens, but also to other foreign antigens. Although by definition patients on immunosuppression cannot be deemed tolerant, some of these recipients may indeed be tolerant of their allografts. Indeed, in a small minority of patients taken off immunosuppressive medications for various reasons, rejection does not occur. However, it is not clear whether these individuals are truly immunocompetent or whether poorly understood immune defects are present. The absence of allograft rejection without the use of immunosuppressive medications seems a reasonable definition, although it fails to account for indefinite graft survival but persistent in vitro T cell reactivity or cases with evidence of immunologic damage on biopsy specimens. Moreover, it evokes questions as to how long tolerance must be present to deserve the name and whether retrospective judgment is really sufficient to make this claim. Although much research is focused on the development of "tolerance assays," at present, no reliable assay exists. The most widely accepted definition for transplantation tolerance currently is the absence of a destructive immune response to the allograft without the need for generalized immunosuppression. This definition will undoubtedly continue to evolve as our understanding of the mechanisms of tolerance improves.
Mechanisms
Transplantation tolerance, similar to selftolerance, is often classified as either central (thymus) or peripheral (extra-thymic lymphoid tissues), although the two need not be considered mutually exclusive. [7] In general, tolerance induction occurs by three basic mechanisms, including deletion, anergy, and regulation/ suppression, although the relative importance of each varies between the two compartments. In the next section, the basic tolerance mechanisms see [Table - 1] will be reviewed, including discussion as to how they may be exploited successfully in clinical transplantation.
Central Tolerance
Central tolerance involves primarily deletional mechanisms analogous to those active during self-tolerance, whereby developing T cells strongly reactive to self in the thymus undergo programmed cell death (apoptosis) and are removed from the T cell repertoire during fetal development. [8] To exploit this mechanism for the induction of transplantation tolerance in adults, in contrast to self-tolerance induction in the fetus, elimination of the preexisting mature T cell population must first occur. Next, expression of donor antigens in the thymus, particularly on the bone marrow-derived dendritic cells important for deletion of developing autoreactive T cells, [9] must be achieved in order to "reeducate" the thymus to delete also those developing T cells reactive to donor antigen.
Clinically, central tolerance induction has been achieved by whole-body irradiation (to remove mature T cells) followed by reconstitution with donor bone marrow (i.e. bone marrow transplantation), which ensures engraftment of donor stem cells in the thymus. Such a state is referred to as chimerism, which is the simultaneous presence of living cells from two distinct genetic backgrounds in one organism. Although this approach is acceptable for patients with life-threatening malignancies, the obligatory myeloablative regimen is far too toxic for the average patient with end stage renal disease. Furthermore, there are theoretical immunologic disadvantages to full allogeneic hematopoietic chimerism that lead to impaired ability to fight infections. [7] These issues have been overcome somewhat through the development of "mixed chimerism," using nonmyeloablative induction regimens followed by repopulation with both donor and recipient hematopoietic cells (including peripheral stem cells). [10 Typical conditioning regimens include depleting T cell antibodies along with various cytotoxic agents, based on protocols with reduced toxicity that were developed for allogeneic stem cell transplantation in elderly patients with hematologic malignancies. [11] The persistence of donor cells among peripheral blood cells, although only a surrogate marker for thymic expression of donor antigen, does correlate well with the achievement of deletional tolerance and can be monitored easily by techniques such as flow cytometry and real-time quantitative polymerase chain reaction. [Figure - 1] shows a brief overview of central tolerance induction and mixed chimerism as it applies to renal transplantation.
Most researchers in the field contend that any clinically successful tolerance strategy in renal allograft recipients will be achieved only if it establishes stable donor hematopoietic chimerism. [12] However, this approach faces major barriers in that the protocol must be mild enough to be tolerated by the average patient yet still allow for routine engraftment of completely mismatched donor cells without generating graft-versus-host disease. To date, no regimen that achieves persistent mixed chimerism in humans can make this claim, and as such, the approach is not yet a clinical reality.
Peripheral Tolerance
Peripheral tolerance mechanisms are designed to control mature T cells that escape thymic deletion during fetal development and exhibit low, but definite autoimmune potential. These mechanisms can be divided into deletional and non-deletional categories, depending on whether cell death occurs in the responding T cell population. As with central tolerance, there is significant interest in finding ways to exploit peripheral tolerance mechanisms to induce transplantation tolerance in the clinical setting.
Veto cells are CD8+ T cells that maintain peripheral tolerance by attacking CD8+ T cells that would otherwise kill them. These cells are present in the bone marrow with increased frequency and may partly explain tolerance in some bone marrow transplant models. Likewise, recipient veto cells may be responsible for the reduction in graft-versushost disease seen with the mixed chimerism approach. It has been demonstrated that veto cells can be generated in high numbers by culture of hematopoietic stem cells obtained from the peripheral blood. [13] It is hopeful that transplantation of such cells will promote mixed chimerism, although this has not yet been demonstrated.
Activation-induced cell death (AICD) is a peripheral tolerance mechanism designed to constrain the unlimited expansion of T cells by antigenic stimulation during the physiologic immune response. AICD can occur by interaction of the apoptosis-inducing Fas (CD95) molecule with its ligand, FasL, on proliferating T cells but also by IL-2 dependent apoptosis. Both mechanisms appear to be more effective with T cells responding later in the immune response, since these cells express more Fas and also have a heightened sensitivity to IL-2. Recent evidence in rodents suggests that T cell apoptosis may be a requirement for the induction of peripheral transplantation tolerance. [14] In these models, certain conventional immunosuppressive agents were shown to inhibit tolerance induction by this mechanism, [15] although these findings have not been duplicated in large animals or humans. The major problem with exploiting AICD for the induction of transplantation tolerance is that this mechanism does not lead to the complete destruction of all antigen-specific T cells, since a subpopulation of memory cells primed for a second response emerges from the initial T cell activation. Future strategies are aimed at accurately identifying this memory T cell population for selective deletion using monoclonal antibodies or other agents.
Peripheral non-deletional tolerance mechanisms have included cells that regulate/ suppress T cell activation or direct mechanisms that induce an actual alteration in the character of responding T cells. Evidence for the existence of regulatory/suppressor cells is indisputable, since animal studies indicate that tolerance can be adoptively transferred to naive recipients (i.e. infectious tolerance). In these numerous studies, regulatory cells have been demonstrated to exhibit both antigen-specific and -nonspecific properties and to exert their suppression by a combination of both contact-dependent and cytokine-dependent mechanisms. Complete characterization of the phenotype has been difficult, but appears to involve production of variable amounts of IL-10, TGF-β, IL-4, IL-5, and IFN-y. It is now clear that the activation state of dendritic cells, the most potent antigen presenting cells of the immune system, influences the type of regulatory cell generated and may explain the diverse phenotypes reported in the literature.
A naturally occurring subset of CD4 + T cells, often called CD4 + CD25 + regulatory T cells, are intimately involved with the regulation / suppression of immune responses. These cells are generated in the thymus, although recent evidence suggests that they can also be generated in the periphery. [16],[17] Animal studies have shown that CD4 + CD25 + regulatory T cells play a role in transplantation tolerance and can prevent allograft rejection. These studies underscore the potential of these cells as a therapeutic tool for the induction of transplantation tolerance in the clinical setting. Specifically, efforts are underway to manipulate the in vivo generation of CD4 + CD25 + regulatory T cells using monoclonal antibodies against T cells or various immunosuppressive agents. Furthermore, several groups are examining the possibility of ex-vivo expansion of these cells for adoptive transfer into transplant recipients. Given what is known about regulatory T cell function in the physiologic state, these putative therapies would not likely be as durable as the central tolerance strategies proposed earlier, but may serve as important adjunctive therapies in concert with other tolerance induction regimens or short-term administration of immunosuppressive medications. Caution must be exercised, however, that the regulation is indeed specific to the antigens of the allograft, since non-specific suppression may lead to the same unwanted side effects of infection and malignancy that plague the use of immunosuppressive medications.
T cell anergy is characterized by an initial T cell stimulus that is insufficient to cause T cell activation but rather causes an alteration such that a fully competent stimulus is no longer effective. Anergy is typically characterized by no specific cytokine production, and recent evidence suggests that anergic T cells may have contact-dependent regulatory properties on other T cells or even on dendritic cells 18,19 Thus, T cell anergy may simply represent a specific subset of cells under the general umbrella of the regulatory / suppressor phenomenon. As with all peripheral mechanisms, efforts are underway to determine the ideal therapeutic approach to induce T cell anergy in antigen-specific responder T cells, which might include antibodies against T cells or manipulation of antigen presentation by altered dendritic cells.
B Cell Tolerance
Autoimmune damage in the body is often caused by high-affinity IgG antibodies, which are known to be dependent on help from T cells. There are circumstances, however, in which B cells can exert reactivity independent of T cells. Various tolerogenic responses of B cells to non-self antigen have been demonstrated and include clonal abortion, anergy and deletion. [20] However, in most cases, preventing self-reactivity in the B cell repertoire is achieved simply by ensuring the absence of T cell help (i.e. T cell tolerance). Recent work has shown that alloantibody production by B cells after allotransplantation is dependent on T cell help. [21] Thus, it appears that any strategy that is successful in B cell tolerance induction within the transplant setting will have as its first requirement the induction of T cell tolerance, as described previously.
| Clinical Approaches | | |
Clearly, no tolerance-inducing strategy is yet ready for application to the general renal transplant population. However, significant resources have been allocated recently in an effort to move tolerance research from the laboratory into the clinical realm. At least three approaches are being undertaken to study the mechanisms of tolerance in this setting, including 1. The study of patients that already display functional tolerance; 2. Immune monitoring of recipients taking immunosuppressive medications; and 3. Prospective drug withdrawal trials.
Certain renal transplant recipients have been weaned successfully from immunosuppressive medications either through medical necessity (life-threatening infections, malignancy etc…) or as a result of patient noncompliance. The Immune Tolerance Network Registry of Tolerant Kidney Transplant Recipients is a multi-center study designed to identify and study this rare group of tolerant patients. Four groups of patients are included: 1. patients off immunosuppressive medications with normal allograft function; 2. patients off immunosuppressive medication with impaired renal function not felt to be immunologic in nature (i.e. drug toxicity, recurrent disease); 3. Patients on minimal immunosuppression (i.e. prednisone alone); and 4. Recipients of kidneys from identical twins. One goal of the study is to use detailed analysis of demographic and clinical data to identify clinical variables associated with the tolerant state. The second goal is to evaluate several putative "tolerance" assays for the purpose of validating those that correlate with the tolerant state. Although a detailed discussion of the various immune monitoring assays is beyond the scope of this review, a brief list of those that are currently being tested is included in [Table - 2]. It is hopeful that studies in actual human subjects will provide insights into the mechanisms of transplantation tolerance that would not be available with animal models alone.
Efforts are also underway to study immune monitoring assays in the general renal transplant population. The goal of these studies is to gather information on the recipient's immune system that would allow the immunosuppressive regimen to be individualized. Clearly, each individual transplant recipient responds differently to immunosuppressive medications, and such an approach may allow significant dose reduction in certain patients. Moreover, this information can also be correlated with various outcomes, such as the absence of rejection, which should be useful in identifying future candidates best suited for enrollment in tolerance induction trials.
Finally, studies are underway that involve normal or increased levels of immunosuppression at the time of transplantation that is withdrawn over time from those recipients with excellent graft function. [22] Renal function is monitored very closely in these subjects, and aggressive biopsy practices are employed to identify and treat all acute rejection episodes. Those recipients who undergo successful withdrawal can then be studied in more detail as described above. Understandably, such an approach results in higher than average acute rejection rates. Since tolerance is generally regarded as an active process, it is hopeful that these episodes serve to induce immunoregulatory mechanisms that persist after successful treatment. However, acute rejection episodes are known to be a significant risk factor for the development of chronic allograft nephropathy and ultimate long-term graft loss. [23] Thus, the success or failure of this bold strategy will only truly be known after lengthy follow-up.
| Conclusions | | |
Although it has been relatively easy to induce transplantation tolerance in rodents, translating these studies into larger animals and humans has proved a more formidable task. Even with the ideal strategy in hand, the lack of a reliable and predictive immune monitoring assay still prevents us from knowing whether tolerance is truly present. Ultimately, we must define achievement of transplantation tolerance in clinical, immunologic and molecular terms. Knowledge gained from current clinical trials will hopefully bring us a little closer to this lofty goal.
| References | | |
| 1. | Billingham RE, Brent L, Medawar PB. Activity acquired tolerance of foreign cells. Nature 1953;172(4379):603-6.  |
| 2. | Womer K, Meier-Kriesche H, Kaplan B. Graft and Patient Survival. In: Matthew R. Weir M, editor. Medical Management of Kidney Transplantation. 1st ed. Philadelphia: Lippincott, Williams & Wilkins; 2005. p. 1-17. |
| 3. | Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4(3):378-83. |
| 4. | Womer KL, Lee RS, Madsen JC, Sayegh MH. Tolerance and chronic rejection. Philos Trans R Soc Lond B Biol Sci 2001;356(1409):727-38. |
| 5. | Womer KL, Sayegh MH. Donor antigen and transplant tolerance strategies: it takes two to tango! J Am Soc Nephrol 2004; 15(4):1101-3. |
| 6. | Salama AD, Remuzzi G, Harmon WE, Sayegh MH. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001;108(7):943-8. |
| 7. | Dong VM, Womer KL, Sayegh MH. Transplantation tolerance: the concept and its applicability. Pediatr Transplant 1999; 3(3):181-92. |
| 8. | Schwartz RS. Shattuck lecture: Diversity of the immune repertoire and immunoregulation. N Engl J Med 2003;348(11):1017-26. |
| 9. | Kamradt T, Mitchison NA. Tolerance and autoimmunity. N Engl J Med 2001; 344(9):655-64. |
| 10. | Sykes M. Mixed chimerism and transplant tolerance. Immunity 2001;14(4):417-24. |
| 11. | Toungouz M, Donckier V, Goldman M. Tolerance induction in clinical transplantation: the pending questions. Transplantation 2003;75(9 Suppl):58S-60S. |
| 12. | Auchincloss H Jr. In search of the elusive Holy Grail: the mechanisms and prospects for achieving clinical transplantation tolerance. Am J Transplant 2001;1(1):6-12. |
| 13. | Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995;1(12):1268-73. |
| 14. | Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999;5(11):1303-7. |
| 15. | Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999;5(11):1298-302. |
| 16. | Akbar AN, Taams LS, Salmon M, Vukmanovic-Stejic M. The peripheral generation of CD4+ CD25+ regulatory T cells. Immunology 2003;109(3):319-25. |
| 17. | Taams L, Vukmanovic-Stejic M, Salmon M, Akbar A. Immune regulation by CD4+ CD25+ regulatory T cells: implications for transplantation tolerance. Transpl Immunol 2003;11(3-4):277-85. |
| 18. | Taams LS, van Rensen AJ, Poelen MC, et al. Anergic T cells actively suppress T cell responses via the antigen- presenting cell. Eur J Immunol 1998;28(9):2902-12. |
| 19. | Lechler RI, Ng WF, Camara NO. Infectious tolerance? Mechanisms and implications. Transplantation 2001;72(8 Suppl):S29-31. |
| 20. | Miller JF. Immune self-tolerance mechanisms. Transplantation 2001;72(8 Suppl):S5-9. |
| 21. | Steele DJ, Laufer TM, Smiley ST, et al. Two levels of help for B cell alloantibody production. J Exp Med 1996;183(2):699-703. |
| 22. | Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003;361(9368): 1502-10. |
| 23. | Womer KL, Vella JP, Sayegh MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin Nephrol 2000;20(2):126-47. |
Correspondence Address:
Karl L Womer
Renal Division, Department of Medicine, University of Florida College of Medicine and Malcom Randall VAMC, Gainesville, Fl 32610-0224
USA
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PMID: 18202504 
[Figure - 1]
[Table - 1], [Table - 2] |
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