American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1005-1011, December 2009

Clinical Transplantation Tolerance: A Myth No More, But…

  • Jamil Azzi, MD
    • ,
  • Mohamed H. Sayegh, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Mohamed H. Sayegh, MD, Transplant Research Center, Brigham and Women's Hospital, Children's Hospital Boston, 221 Longwood Ave, Boston MA 02115

Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA

published online 12 October 2009.

Article Outline

More than 55 years after the description of the phenomenon of acquired immunologic tolerance to transplant antigens by Medawar and colleagues, the holy grail of transplantation is a myth no more. Establishment of the Immune Tolerance Network in 1999 changed the approach used to achieve clinical tolerance by translating advances in the field of immunology in general and in tolerance in particular from experimental animal strategies into human clinical trials, and initial results have been promising. Despite these advances, scientific and operational challenges still face the transplantation community and affect progress. Overcoming those challenges is a shared responsibility of scientists, transplant professionals, and general nephrologists alike. Achieving tolerance could not only revolutionize the field of transplantation through avoidance of toxicity associated with immunosuppressive agents, but also influence the treatment of autoimmune diseases, in which the immune system attacks self, as well as cancer, in which tolerance of the immune system toward malignant cells may permit disease development and progression.

 

More than 55 years ago, a report published in Nature by Billingham et al1 widened the horizons of modern medicine by describing the phenomenon of acquired immunologic tolerance to transplant antigens. Shortly thereafter, one of the first kidney transplants was performed at the Peter Bent Brigham Hospital in Boston, MA, by a team headed by Joseph Murray, a plastic surgeon, that included John Merrill, a nephrologist.2 These 2 great milestones laid the foundation for tremendous advances in the field of transplantation immunology during the past 5 decades.3 Together, they launched a worldwide search for the holy grail of transplant tolerance, which is defined as the absence of pathologic immune response against a graft in an immunocompetent host not using maintenance immunosuppressive drugs.4 In this review, we highlight recent advances in the field of immunologic tolerance in organ transplantation that have made that holy grail a myth no more. For the sake of clarity, terminology used in this article is defined in the glossary (Box 1).

The Shaul G. Massry Distinguished Lecture is delivered at the National Kidney Foundation's annual Spring Clinical Meetings. This lectureship was established to honor Dr Massry for his scientific achievements and his contributions to the kidney health care community and the National Kidney Foundation. The 2009 lecturer was Mohamed H. Sayegh, MD, and his remarks form the basis for this article.

Box 1. Glossary

Immunologic tolerance: a state of immunologic unresponsiveness toward a given set of antigens in an immunocompetent individual

Transplantation tolerance: the absence of pathologic immune response against a graft in an immunocompetent host not using maintenance immunosuppressive drugs

Mixed lymphohematopoietic chimerism: the state after bone marrow transplant in which hematopoietic cells of donor and recipient origin coexist

Nonmyeloablative bone marrow transplant: allogeneic bone marrow transplant that uses lower doses of chemotherapy and/or radiation with the goal to make room for the donor cells and prevent their rejection without destroying the recipient's bone marrow

Regulatory T cell (Treg): T lymphocyte that turns off specific immune responses

Mixed lymphocyte reaction (MLR): the proliferative response that occurs when lymphocytes from 2 individuals are cultured together, as the result of reactions of T cells of 1 individual to MHC antigens on the other individual's cells

Cytotoxic T lymphocyte (CTL): a T lymphocyte (which usually expresses CD8) that kills its target cell on recognizing complexes of peptides and MHC molecules on the target-cell membrane

Central deletion: a mechanism of immune tolerance using lymphoablative treatments to create a mixed hematopoietic chimeric state. In this instance, donor cells seed the thymus, and maturing donor-reactive T-cell clones are deleted through intrathymic apoptosis

Peripheral deletion: another mechanism of immune tolerance by which donor-reactive cells can undergo apoptosis outside the thymus, in either the allograft itself or in draining lymph nodes

Abbreviation: MHC, major histocompatibility complex.

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The Rise of a New Era in Transplantation 

Early Efforts to Achieve Transplant Tolerance 

After the pioneering era of Peter Medawar, John Merrill, Joseph Murray, and others, a second era can be described in which the major advances in immunology focused on the development of strategies to induce tolerance in experimental animal models. In addition, although several reports described the phenomenon of immunologic tolerance in some humans, these interventions were not rigorously attempted in controlled trials.5 During the pre-1999 era, tolerance was reported first by a group from Stanford in 3 patients who underwent total-body lymphoid irradiation before receiving a cadaveric kidney transplant.6 Soon thereafter, we reported 2 leukemic patients complicated by end-stage renal disease (ESRD) who received a bone marrow transplant. Each of these patients subsequently received a successful kidney transplant several years later from their bone marrow donor without using immunosuppressive drugs, except for a low dose of prednisone for other indications.7 Similarly, a team at the Massachusetts General Hospital treated a patient with multiple myeloma complicated by ESRD with both a bone marrow and kidney transplant from the same donor, inducing mixed lymphohematopoietic chimerism (defined as the persistence of donor hematopoietic cells in the recipient). This has been suggested to modulate immune responsiveness to donor alloantigens as a mechanism of transplant tolerance.8 Finally, some transplant recipients would play Russian roulette by discontinuing their immunosuppressive medications, with a lucky few serendipitously winning tolerance.9

Successes in Liver Transplant Tolerance 

The liver is considered an immune-privileged organ characterized by an anatomic structure believed to facilitate mixed chimerism through bidirectional interaction of donor and recipient leukocytes, resulting in elimination of alloreactive T cells to donor and recipient cells consecutively.10 These observations encouraged prospective drug withdrawal programs in > 90 liver transplant recipients between 1992 and 1996, with very promising results for the transplant community at the time.11 After this initial trial, a smaller cohort of 18 patients had immunosuppression therapy withdrawn at King's College, London, with 28% of patients reported completely free of medications at 3 years.12

Operational liver tolerance trials have continued to emerge in the last few years. Takatsuki et al13 in Japan successfully achieved complete withdrawal of tacrolimus therapy in 38% of their 63 liver transplant recipients, and a Kyoto group reported the withdrawal of immunosuppressants in 87 of 659 (15%) children who underwent living donor liver transplant between 1990 and May 2005.14 Results from a Pittsburgh group have been particularly notable, with a mean time off immunosuppression therapy > 10 years in a cohort of 48 liver transplant recipients. Return to immunosuppression therapy has been rare (1 of 48 patients).15

The Era of the Immune Tolerance Network 

A new era emerged with the rise of the new millennium after establishment of the ITN (Immune Tolerance Network: www.immunetolerance.org), a clinical research consortium founded by the US National Institutes of Health in 1999 for the purpose of focusing efforts on the goal of achieving immune tolerance therapies. The formation of this consortium has resulted in many clinical trials, not only in islet and solid-organ transplant, but also in autoimmune disease and allergy/asthma (Table 1).

Table 1. Recent and Ongoing Clinical Trials of Immune Tolerance Therapies
ProcedureTolerance ProtocolStudy Status
Islet transplantEdmonton protocol of steroid-free immunosuppressionCompleted; 44% (16/36) insulin free at 1 y; 14% (5/36) insulin free at 2 y16
Kidney transplantAlemtuzumab,a tacrolimusb for 60 d, sirolimus (rapamycin) for 1 yActive
Kidney transplantDaclizumab, LEA29Y (belatacept), MMF, sirolimus for 1 yActive
Kidney transplantAlemtuzumab, donor stem-cell infusion, tacrolimus/sirolimus and MMF for 1 yActive
Kidney & bone marrow transplantCyclophosphamide, MEDI-507 (siplizumab), 7 Gy thymic irradiation, donor bone marrow, cyclosporine for 60 dCompleted; 4/5 patients withdrawn from all immunosuppressants18
Kidney & bone marrow transplant for myeloma patientsCyclophosphamide, ATG, 7 Gy thymic irradiation, donor bone marrow, cyclosporine for 36-60 dCompleted; all 6 patients withdrawn from all immunosuppressants17
Liver transplantAlemtuzumab, tacrolimus slowly withdrawnActive
Liver transplantGradual withdrawal of maintenance immunosuppression in patients who underwent living donor liver transplants as childrenActive
Liver transplantAlemtuzumab vs 3 mo of steroids followed by tacrolimus slowly withdrawnActive

Abbreviations: ATG, antithymocyte globulin; MMF, mycophenolate mofetil.

aHumanized anti-CD52 antibody (Campath-1H; Berlex Laboratories, www.berlex.com).

bPrograf (Astellas Pharma US Inc, www.astellas.us).

One of the first fruits born of the ITN was the publication from the Massachusetts General Hospital group of a case series composed of 6 patients with multiple myeloma and ESRD who received simultaneous kidney and bone marrow transplants from HLA-identical sibling donors after a nonmyeloablative regimen. Immunosuppressive drugs were completely withdrawn within 2 months after transplant. Chimerism was transient in 4 patients. One patient experienced rejection. This was treated successfully, and immunosuppressive drugs were withdrawn successfully in that patient 1 year later. Two other patients developed graft-versus-host disease, and immunosuppressive medications were resumed.17

A recent New England Journal of Medicine report published by the same Massachusetts General Hospital group reported on 5 patients with ESRD with combined bone marrow and kidney transplants from HLA single-haplotype–mismatched living related donors.18 They used a nonmyeloablative preparative regimen with cyclophosphamide at days −5 and −4 with respect to transplant; humanized anti-CD2 monoclonal antibody on days −1, 0, and 1; and intravenous cyclosporine and thymic irradiation on day −1. They intravenously infused donor bone marrow after the kidney transplant, trying to induce mixed chimerism. One patient developed humoral rejection that required modifying the protocol for future patients to induce B-cell depletion with monoclonal antibody against CD20 (rituximab) on days −7 and −2. The other 4 recipients discontinued immunosuppressive therapy at 9-14 months after transplant with stable renal function, now going on > 6 years for patients 1 and 2 and > 4 and 3 years for patients 4 and 5, respectively (B. Cosimi, personal communication, July 2009). Interestingly, although the chimerism induced by infusion of the bone marrow transplant was transient, tolerance persisted. Hypothesized mechanisms include elimination of cells reactive to donor antigens in the thymus (called central deletion) or generation of regulatory T cells with high expression levels of FOXP3 (a marker of regulatory T cells) in the renal allograft protocol biopsy specimens.18 Close follow-up of these patients is necessary to understand the impact of losing the lymphohematopoietic mixed chimerism and its effect on tolerance, the risk of graft-versus-host disease, and the emergence of other types of rejection, for example, humoral rejection.

In the same New England Journal of Medicine issue, a Stanford group described a recipient of a combined kidney and hematopoietic cell transplant from an HLA-matched donor followed by total lymphoid irradiation and antithymocyte globulin with > 2 years of follow-up with no episodes of rejection or graft-versus-host disease.19

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Challenges in Translating Tolerance Strategies Into the Clinic 

The lack of reliable assays to assess immune function is the most significant challenge to develop clinical tolerance strategies.20 Given that acquired tolerance is weaker than natural tolerance and also may be transient, long-term monitoring is vital.21

Many immune function assays have been developed during the last decade, but none can accurately predict the development of tolerance.22 Accordingly, we still rely on measuring drug levels of immunosuppressive agents (which affect individuals' immune systems differently), and we evaluate graft function (usually a late marker for events).

Currently available assays can be antigen specific, meant to evaluate donor-specific T-cell responses against recipient antigens by measuring either: (1) proliferation of donor T cells in a mixed lymphocyte reaction, (2) lysis of recipient T cells in a cytotoxic T-lymphocyte assay,9 or (3) production of interleukins with either an enzyme-linked immunosorbent assay or enzyme-linked immunospot assay.23 The transvivo delayed-type hypersensitivity assay uses an immune-deficient mouse as an “in vivo milieu” for the interaction between donor T cells and recipient antigens. T Cells and antigens are injected into the footpads of the mice, causing swelling that is quantified relative to the level of sensitivity that can be measured using a caliper.24 Tetramer technology also may be used to detect the T-cell receptors that are specific for the recipient peptide–major histocompatibility complex molecule complex.25 The classic pretransplant cross-match is still used to detect donor-specific antibodies.

Assays also may be non–antigen specific, measuring regulatory cells, such as the CD4+CD25high T cells known as Tregs,26 plasmacytoid dendritic cells that were reported to promote a type 2 T-helper cell–type response that is more tolerogenic.27 An assay commercialized as ImmunoKnow (Cylex Inc, www.cylex.net) measures T-cell response to a nonspecific polyclonal stimulus by quantifying intracellular adenosine triphosphate production as a marker of the level of cell immune function.28 Another revolutionary measure is a gene signature or gene expression profiling, recently explored by identifying a number of genes differentiating a tolerant from a nontolerant recipient with high accuracy.29, 30 Finally, proteomics, which studies protein expression, can be a necessary complement to gene expression because levels of protein synthesis may not correspond well to measured amounts of the respective messenger RNA transcripts31 (Box 2).

Box 2. Types of Immune Function Assays

Antigen-specific assays
T-Cell alloreactivity:
-Proliferation of donor T cells in MLR
-Lysis of recipient T cell in CTL assay
-Production of cytokines in ELISA or Luminex or ELISpot assays
-Transvivo delayed-type hypersensitivity
Humoral immune responses:
-HLA and non-HLA alloantibodies
Non–antigen-specific assays
Expression profiling of cellular surface markers:
-Flow cytometry for regulatory T cells
-Flow cytometry for plasmacytoid dendritic cells
Measuring T-cell response to nonspecific polyclonal stimulus:
-Intracellular ATP production
RNA analysis (eg, microarrays) and proteomics:
-Identify signature of tolerance

Note: Luminex (www.luminexcorp.com) is a proprietary fluorescent bead immunoassay.

Abbreviations: ATP, adenosine triphosphate; MLR, mixed lymphocyte reaction; CTL, cytotoxic T lymphocyte; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunosorbent spot.

Another major obstacle in developing clinical tolerance is the lack of the ideal animal model that will translate accurately in humans. For example, strategies in rodents have been unsuccessful in nonhuman primates32, 33, 34 and, in turn, may not be applicable in humans.35, 36 Those significant immunologic differences mainly manifest in the proportion of memory and immunologically naive T cells.32 Rodents, for example, which are considered immunologically naive with a lower proportion of memory cells than primates or humans, respond successfully to many costimulatory blockade strategies that fail when used in humans.34 However, memory cells are very resistant to depletion therapy, which may deplete regulatory cells, promoting expansion of the memory T-cell compartment and making tolerance induction even more difficult.37

These unsuccessful outcomes in humans complicate selection of the best strategy to induce tolerance. Is central or peripheral deletion in association with drug minimization the answer, or does a completely novel therapy need to be developed?21 Evolving data incriminate infectious agents through stimulation of Toll-like receptors in preventing and reversing tolerance.38, 39, 40 Toll-like receptors, expressed on a variety of cell types, such as endothelial cells, epithelial cells, macrophages, neutrophils, and antigen-presenting cells, have a major role in innate immunity by recognizing different pathogens and differentiating self from nonself.41 In antigen-presenting cells exposed to an infection, Toll-like receptors stimulate cell maturation by increasing expression of CD80, CD86, and major histocompatibility complex class II antigens, which enhances T-cell responses, directly inducing survival and proliferation of CD4 cells42 and allogeneic CD8 T cells.40 This may explain the differences in resistance to tolerance protocols among transplanted organs because organs that are most exposed to infectious agents tend to be the most recalcitrant.

Another scientific nonimmunologic challenge facing the transplantation community is the best end points to use in a clinical trial. Coupling observation of short-term outcomes (1-year survival) with longer term results when infectious and malignant complications are most likely to occur (2-3 years or beyond) is necessary to ensure safety.

Furthermore, other operational challenges can be difficult to overcome. We need to reach consensus on when to move from a pilot study to a larger trial without exposing patients to intensive protocols if long-term success is unlikely.21 Similarly, it is extremely important to decide on the best management strategy for patients in tolerance trials who experience organ rejection: whether to withdraw them from the trial and return them to conventional therapy or modify therapeutic strategies according to a specific protocol.

The most challenging issue facing modern medicine today, including our quest for tolerance strategies, is ethics. One major issue is eligibility criteria. This is particularly notable for age, given the recognition that children receiving organ transplants may derive the greatest benefit from immunosuppression withdrawal because of their potential longer exposure to immunosuppression, but may derive the greatest risk because a failed organ in a child carries a worse long-term prognosis than in an adult because of sensitization and compromise of a future transplant. A second issue is choosing a suitable organ for these clinical trials given that the consequences of failed liver, heart, and lung transplants are acutely life threatening. Should we compromise a living donor organ or would a cadaveric organ for our initial trials be more appropriate? These issues require collaboration and consensus-building among all members of the transplantation community. ITN began this initiative by presenting a platform on which to share ideas.

Diverging interests between pharmaceutical companies and the transplantation community regarding tolerogenic strategies may impair progress because the pharmaceutical industry may be perceived as being interested in keeping patients on maintenance immunosuppressive medication therapy. Therefore, cooperation between pharmaceutical companies that develop and market agents to induce tolerance and the transplantation community is essential for success in achieving the goal of tolerance.

Facilitating future success in refining tolerance-inducing strategies is a responsibility shared by scientists and transplant and general nephrologists alike. Resistance to minimizing or halting immunosuppression is an issue for both patients and their physicians, especially when patients currently are stable with maintenance or low-dose immunosuppression. Rightfully, patients and physicians both ask: Is low-dose immunosuppression really an alternative to complete withdrawal from drug therapy? Do low-dose safe levels exist?

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Conclusion 

Improving our communication and collaboration is integral to achieving tolerance, which will have a direct impact on the morbidity and mortality of transplant recipients, mainly through avoidance of toxicity associated with immunosuppressive agents. Nonspecific immunosuppression increases the risk of malignancies, infections, and metabolic diseases, such as diabetes and dyslipidemia, thus increasing the rate of cardiovascular mortality.43 Furthermore, calcineurin inhibitors have been incriminated in shortening graft survival, increasing the demand for retransplant, and worsening the organ shortage.44

Beyond transplantation, better understanding the mechanics of tolerance could profoundly influence the treatment of autoimmune diseases, such as type 1 diabetes and lupus, in which the immune system attacks self. In addition, therapeutic approaches to cancer might evolve by better understanding the tolerance of the immune system toward malignant cells.

Implementation of a successful safe tolerance regimen also has the potential to create a framework for new treatments of genetic diseases through stem cell therapy, reestablishing islet cell transplant in patients with type 1 diabetes, and launching regenerative medicine by allogeneic stem cell transplant, for which the achievement of tolerance is not a mere option, but an absolute necessity.

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Acknowledgements 

Financial Disclosure: Dr Sayegh is a consultant to Genzyme, but has no financial interest related to the subject matter of this article. Dr Azzi has no relevant financial interests.

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 Originally published online as doi:10.1053/j.ajkd.2009.08.005 on October 12, 2009.

PII: S0272-6386(09)01079-8

doi:10.1053/j.ajkd.2009.08.005

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1005-1011, December 2009

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