ITN - Solid Organ Transplantation

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Solid Organ Transplantation Research

While the immunosuppressive drugs developed in the past two decades have improved the short-term survival of organ allografts (1), the effects of these regimens on long-term outcome has not yet been determined (2). A significant shortcoming of current anti-rejection therapies is that recipients require life-long treatment on an immunosuppressive regimen and are left at greater risk of serious side effects(1, 3). Thus, it is of paramount importance that tolerance strategies be developed whereby the destructive alloimmune response is stopped, while maintaining general immune competence (4).

There are a number of examples where tolerance is clinical transplantation has been shown to exist. A small fraction of patients who have terminated their maintenance immunosuppression seem to maintain a functioning graft (5). The ITN is currently conducting tolerance assay studies in one such cohort of liver transplant patients and will begin compiling a list of similar kidney transplant recipients in the near future. In addition, techniques using induction therapy with whole body radiation (6, 7) and those first receiving bone marrow transplants with kidneys from the same donor appear to have induced an operational tolerance(8, 9). The ITN is also actively investigating these methods in current trials.

Current areas of emphasis are as follows:

1) IMMUNOSUPPRESSIVE DRUG WITHDRAWAL

Biomarkers for successful immunosuppression withdrawal
The initial goal of studies in liver and kidney transplantation is the reduction or elimination of use of long-term maintenance immunosuppression, in order to alleviate its associated complications and high costs. The Network is currently supporting studies aimed at developing and validating assays to predict the outcome of immunosuppression withdrawal and the ultimate establishment of tolerance. This involves the identification of that group of patients who maintain functional liver and kidney grafts despite discontinuation of all immunosuppressive therapy.

2) NOVEL IMMUNOTHERAPEUTIC STRATEGIES IN CONJUNCTION WITH CALCINEURIN-INHIBITOR-FREE PROTOCOLS

The Network aims to test potential tolerance induction strategies that do not include calcineurin inhibitors, against a backdrop of immunosuppression in both kidney and liver transplantation. As surrogate markers are identified via collaborative efforts with the Tolerance Assay Subgroup, further withdrawl of immunosuppression is anticipated. Novel immunotherapeutic agents which have shown promise are of great interest to the Network, especially in unique combinations:

Blockade of TCR/Co-receptor Signals
Blockade of Accessory/Costimulatory Signals

3) THERAPEUTIC ESTABLISHMENT OF HEMATOPOIETIC CHIMERISM

The ITN places a high emphasis on studies designed to promote donor hematopoietic engraftment independent of the use of irradiation or depletion. Those strategies involving appropriate combination treatments with inductive T-cell directed therapy, higher doses and costimulatory blockade, as a means of eliminating the need for recipient radiation conditioning, are of significant interest to the Network. Several studies examining mixed chimeric approaches to tolerance are currently under investigation.

References
1. Denton, MD, Magee, CC, Sayegh, HH. Immunosupressive strategies in transplantation. Lancet 353: 1083-1091, 1999.

2. Womer, KL, Vella, JP, Sayegh, MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin Nephrol 220: 126-147, 2000.

3. Kasiske BL, Chakkera HA, Roel J. Explained and unexplained iscaemic heart disease risk after renal transplantation. J Am Soc Nephrol 11: 1735-43, 2000. [Full Text]

4. Suthanthiran M. Transplantation tolerance: Fooling mother nature. Proc Natl Acad Sci USA 93: 12072-5, 1996. [Full Text] (pdf)

5. Burlingham, WJ et al. Microchimerism linked to cytotoxic T lymphocyte functional unresponsiveness (clonal anergy) in a tolerant renal transplant recipient. Transplantation 59: 1147-55, 1995.

6. Strober, S et al. Clinical transplantation tolerance twelve years after prospective withdrawal of immunosuppressive drugs: studies of chimerism and anti-donor activity. Transplantation 69: 1549-54, 2000. [Full Text] (pdf)

7. Strober, S et al. Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation. N Engl J Med 321: 28-33, 1989.

8. Sayegh, MH et al. Immunologic tolerance to renal alografts after bone marrow transplants from the same donor. Ann Intern Med 114: 954-5, 1991.

9. Spitzer TR et al. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation 68: 480-4, 1999. [Full Text] (pdf)