Transplantation tolerance: a journey from ignorance to memory

Fadi G. Lakkis

Section of Nephrology, Department of Internal Medicine and Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

Correspondence and offprint requests to: Fadi G. Lakkis, MD, Yale University School of Medicine, Section of Nephrology, 333 Cedar Street, PO Box 208029, New Haven, CT 06520-8029, USA. Email: fadi.lakkis{at}yale.edu

Keywords: cytokines; memory T lymphocytes; primary immune response; transplantation tolerance

Transplantation tolerance can be defined as long-term allograft survival in the absence of continuous immunosuppressive therapy. Implicit to this definition is that tolerant recipients of organ transplants are unresponsive to donor antigens but maintain reactivity to other (third-party) antigens. In other words, a tolerant patient is capable of mounting an effective immune response against microbial pathogens but is incapable of rejecting the transplanted organ.

Despite a wealth of information on how tolerance to self-antigens is maintained (Figure 1), the induction of tolerance to a transplanted organ remains elusive because of several biological barriers. These barriers include the relatively large magnitude of the alloimmune response, the limitations of peripheral tolerance mechanisms, and the unavoidable fact that immune responses to foreign antigens, by virtue of evolutionary design, are destined to generate immunologic memory [1]. Here, I would like to relay the trials and tribulations of my research group, as well as those of others, to understand how tolerance to a transplanted organ can be achieved.



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Fig. 1. Mechanisms of self-tolerance: both central (thymic) and peripheral (extra-thymic) mechanisms mediate tolerance to self-antigens. Central mechanisms include deletion of auto-reactive T lymphocytes and generation of regulatory T cells. Autoreactive T cells that escape thymic deletion are subject to peripheral tolerance mechanisms (deletion, regulation and anergy).

 
Introduction

When faced with a daunting scientific quest, it is perhaps best to start by laying out a simple road map of the journey that lies ahead. A useful road map in the pursuit of transplantation tolerance is that of the primary immune response (Figure 2). Upon exposure to a foreign antigen, whether a potentially lethal virus or a life-saving organ transplant, antigen-specific T cells proliferate extensively (the expansion phase) and acquire effector functions that allow them, with the help of B lymphocytes and other mononuclear cells, to eliminate the foreign intruder. T cell expansion, however, does not continue indefinitely but comes to a quick halt as autoregulatory mechanisms ensure that most effector T cells generated during the immune response are eliminated by apoptosis (the death phase). The few lucky T cells that survive the death phase become long-lived memory T cells that confer life-long protection against the foreign antigen (the memory phase). Therefore, the central question in the quest for transplantation tolerance is how to coerce an immune response determined to generate T cell memory into a state of blissful unresponsiveness.



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Fig. 2. Schematic representation of the primary immune response: upon encounter with antigen-presenting cells within secondary lymphoid organs (point A), antigen-specific T lymphocytes proliferate exponentially and generate effector cells. Regulatory mechanisms (point B), however, ensure that most effector T cells undergo apoptosis. The few antigen-experienced T lymphocytes that survive become memory T cells. Productive immune responses to foreign antigens, therefore, are destined to generate immunologic memory.

 
Ignorance is bliss

To tackle this central question, we first asked whether preventing the primary immune response from occurring within the correct anatomical context leads to tolerance. In other words, does interfering with the primary step required for launching the adaptive immune response, the interaction of antigen presenting cells (APC) with T cells (Figure 2, point A), cause immunologic unresponsiveness? To answer this question, we transplanted fully vascularized cardiac allografts to mice that lack secondary lymphoid organs [2]. Secondary lymphoid organs (the spleen, lymph nodes and mucosal lymphoid tissues) are the seat of primary immune activation as they provide the optimal environment for APC–T cell interaction. As expected, we found that such mice are unable to reject their allografts because they cannot mount primary immune responses. Alloreactive T cells in these recipients, however, remained immunocompetent as they quickly mediated allograft rejection when transferred to an immunodeficient host that had a full complement of secondary lymphoid organs. Therefore, chance encounter between T cells and alloantigens outside the context of secondary lymphoid organs does not lead to T cell tolerance but, instead, the transplanted organ is ignored and the alloreactive T cells remain functionally intact. This finding implies that clinical strategies based on global immunosuppression, which prevents primary T cell activation, are unlikely to achieve tolerance.

Cytokines: friends or foes?

It is generally assumed that blocking mitogenic T cell cytokines, particularly interleukin-2 (IL-2), not only prevents the proliferation of activated T cells but also coerces these cells to die or become anergic. Therefore, we and others asked whether targeting the expansion phase of the alloimmune response (Figure 2) leads to transplantation tolerance by studying allograft survival in mice that lack IL-2. The results of these experiments were completely unexpected. First, allograft rejection occurred unhindered in the absence of IL-2 [3,4]. Secondly, long-term allograft survival or tolerance could not be induced in IL-2-deficient mice, even when effective immunosuppressive or immunomodulatory agents were administered [4,5]. Unknown to transplant immunologists at the time was the fact that IL-2 plays a dual in vivo role. On one hand, it is an important but dispensable T cell mitogen. On the other hand, it is indispensable for preparing activated T cells for apoptosis, a phenomenon often referred to as activation-induced cell death (AICD) [4]. The role of IL-2 in mediating AICD cannot be substituted for by other T cell mitogens [6]. In addition to IL-2, interferon-{gamma} and perforin, which were initially believed to be essential mediators of rejection, turned out to be critical for down-regulating alloimmune responses [7,8]. Therefore, conventional immunosuppressive strategies, which block cytokine production or function, specifically that of IL-2, are unlikely to facilitate tolerance induction but, instead, may hinder it.

Undesirable memories

A cardinal feature of the adaptive immune response is its ability to generate long-lived populations of memory T lymphocytes (Figure 2) [9]. Memory T cells are specific to the antigen encountered during the primary immune response and react rapidly and vigorously upon re-encounter with the same antigen. Memory T cells that recognize microbial antigens provide the organism with long-lasting protection against potentially fatal infections. On the other hand, memory T cells that recognize donor alloantigens jeopardize the survival of life-saving organ transplants [10]. Memory T cells constitute a formidable hurdle to tolerance induction because they have several functional advantages over their naïve counterparts: they live much longer, have access to both lymphoid and non-lymphoid tissues and have much less stringent activation requirements. Using a murine model of heart transplantation, we recently addressed the anatomic requirements for the activation of allospecific memory T cells. We found that, unlike naïve T cells, antigen-experienced memory T cells mount a productive immune response that leads to allograft rejection and beget more memory T cells independent of secondary lymphoid organs [11]. As little as a few thousand allospecific CD8 memory T cells were able to migrate directly to the allograft and mediate its rejection in an immunodeficient host that lacks secondary lymphoid tissues. The memory T cell response in these experiments could not be suppressed by agents that effectively block naïve T cell costimulation, hinting at the formidable challenge that lies ahead of us if we were to successfully prevent allospecific memory responses. Equally surprising was our finding that the long-term maintenance of CD8 memory T cell populations is inhibited by IL-2 [12], again indicating that IL-2 blockade may hinder the induction of stable tolerance.

Concluding remarks

The journey towards transplantation tolerance has been full of surprises. We have come to realize that T cell activation in the presence of IL-2 is a pre-requisite for tolerance induction, and that memory T cells remain a major hurdle to achieving donor-specific immunologic unresponsiveness in transplant recipients. Perhaps tolerance will be achieved only after we carefully assess our current understanding of the alloimmune response. We can only hope that through further research our ignorance will one day turn into memorable scientific reality.

Acknowledgments

This editorial is based on a lecture by the same title given at the 2002 annual meeting of the American Society of Nephrology (Young Investigator Award and Address).

Conflict of interest statement. None declared.

References

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  2. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 2000; 6: 686–688[CrossRef][ISI][Medline]
  3. Steiger B, Nickerson PW, Steurer W, Moscovitch-Lopatin M, Strom JB. IL-2 knockout recipient mice reject islet cell allografts. J Immunol 1995; 155: 489–498[Abstract]
  4. Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Impaired alloantigen-mediated T cell apoptosis and failure to induce long term allograft survival in interleukin-2-deficient mice. J Immunol 1998; 161: 1659–1663[Abstract/Free Full Text]
  5. Wells AD, Li XC, Li Y et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5: 1303–1307[CrossRef][ISI][Medline]
  6. Dai Z, Arakelov A, Wagener M, Konieczny BT, Lakkis FG. The role of the common cytokine receptor {gamma} chain ({gamma}c) in regulating IL-2-dependent, activation-induced CD8+ T cell death. J Immunol 1999; 163: 3131–3137[Abstract/Free Full Text]
  7. Konieczny BT, Dai Z, Elwood ET et al. IFN{gamma} is critical for long term allograft survival induced by blocking the CD28 and CD40L T cell costimulation pathways. J Immunol 1998; 160: 2059–2064[Abstract/Free Full Text]
  8. Bose A, Kokko KE, Inoue Y, Lakkis FG. Cutting edge: perforin down-regulates CD4 and CD8 T cell-mediated immune responses to a transplanted organ. J Immunol 2003; 170: 1611–1614[Abstract/Free Full Text]
  9. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2: 251–262[CrossRef][ISI][Medline]
  10. Heeger PS, Greenspan NS, Kuhlenschmidt S et al. Pretransplant frequency of donor-specific, IFN-{gamma}-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection epidodes. J Immunol 1999; 163: 2267–2275[Abstract/Free Full Text]
  11. Chalasani G, Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci USA 2002; 99: 6175–6180[Abstract/Free Full Text]
  12. Dai Z, Konieczny BT, Lakkis FG. The dual role of interleukin-2 in the generation and maintenance of CD8+ memory T cells. J Immunol 2000; 165: 3031–3036[Abstract/Free Full Text]




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