Transplantation More questions than answers Editorial overview Hugh Auchincloss Jr* and Kathryn .I Woodt Addresses *Transplantation Unit, Surgical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; e-mail: [email protected]
tNuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; e-mail: [email protected]
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mation about the mechanisms or the consequences of daclizumab therapy. The data from the clinical trials did not show a higher rate of complications involving cytomegalovirus or other infections but it also did not suggest that tolerance developed to the donor's antigens. On the other hand we do not yet know what effect this treatment will have on other types of immune responses, such as a child's future ability to respond to environmental pathogens encountered for the first time during therapy with anti-IL2R antibodies.
Abbreviations IL-2R IL-2 receptor NK natural killer
Strategies for tolerance induction in nonhuman primates
Current Opinion in Immunology 1998, 10:505-506
Introduction The six articles in this section cover a broad range of topics in transplantation immunology. Each of them deals with an area where recent progress in the field has been substantial; however, because they deal with new findings, inevitably each article raises more questions than it answers. This overview highlights some of the questions that still remain.
Therapy using antibodies against the IL-2 receptor Waldmann and O'Shea (pp 507-512) describe the development of the monoclonal antibody called daclizumab - - that recognises the IL-2 receptor (IL-2R) - - and its approval for clinical use by the Food and Drugs Administration. In addition, they outline the molecules involved in signaling by the IL-2R, which may themselves become targets for immunosuppressive therapy in the future. The approval of the new antibody was based on evidence that its use could reduce the rate of rejection episodes to about 20%. This achievement raises the question of what measure should be used in the future to approve new immunosuppressive agents, since it will be both statistically and medically difficult to achieve results that are significantly better than this without increasing the number of complications. Already trials are underway that attempt to use the new antibody to replace other immunosuppressive agents, with the understanding that the rate of rejection may be higher but that patients may still obtain a net benefit by avoiding additional drug therapy. Measuring that benefit objectively presents a new and exciting challenge to teams attempting to design informative clinical trials to evaluate new immunosuppressire agents. The concept underlying the use of this anti-IL-2R antibody is that only activated T cells will be targeted by the treatment. In practice, however, we have very little infor-
While the introduction of a new nonspecific immunosuppressive agent occurred at the clinical level, preclinical trials in several laboratories - - as described by Hamawy and Knechtle (pp 513-517) - - focused on efforts to achieve tolerance for organ transplantation. It is exciting that several independent laboratories, using a number of different strategies, have shown that long-term survival of organ transplants can be achieved without long-term use of conventional immunosuppressive agents and that this can be done in nonhuman primates rather than just in rodents. It is not clear, however, which (if any) of these strategies is ready for clinical application: in some cases, the conditioning required for tolerance induction may be too toxic; in others the reagents supposedly promoting tolerance may require on-going administration over the long term; in others the 'tolerance' achieved may not prevent chronic rejection. As many investigators have recognized, the difficulty in introducing strategies for tolerance into clinical practice stems in part from the outstanding success - - at least in the short term - - o f organ transplantation today. Thus, new strategies must have near-perfect success, with minimal short-term toxicity, before their long-run benefits can begin to be examined. A critical f e a t u r e - for all of the tolerance-inducing strategies being tested in nonhuman primates - - is the lack of markers for determining when such strategies have been successful, short of actually detecting graft rejection. Clearly the measurement of microchimerism is not a satisfactory 'tolerance assay' and as yet no other test has been identified in primates that can achieve this purpose.
Infectious tolerance One possible route to a tolerance assay may be through a better understanding of the mechanisms involved. Cobbold and Waldmann (pp 518-524) describe the recent evidence that has been obtained regarding the mechanisms of 'infectious tolerance' or what might be referred to as 'dominant suppression'.
As Cobbold and Waldmann indicate, the evidence that a T cell response may be immunosuppressive is now substantial; furthermore, the p h e n o m e n o n of linkage strongly suggests that this suppression is antigen-specific rather than receptor-specific. While many investigators have jumped to the conclusion that Th2 responses might be controlling T h l (rejection-promoting) cytokine production, Cobbold and Waldmann demonstrate the many weaknesses of this view. Instead they develop the hypothesis that IL-10 and transforming growth factor (TGF)-~, produced by Th3 cells (also known as Trl cells), may be the critical suppressive factors. T h e hypothesis is attractive, especially because it is simple enough to be tested; however, in addition to testing this theory, it will be important to learn how to harness the suppressive response, how to strengthen it to deal with more powerful immune responses than those that have been studied so far and whether the enhanced production of T G F - ~ might promote chronic rejection - - as some investigators have suggested.
The endothelium At least in part, the three remaining articles in this overview reflect the on-going pursuit of xenotransplantation. Although the article on interactions between T lymphocytes and endothelial cells - - written by Briscoe, Alexander and Lichtman (pp 525-531) - - does not mention xenotransplantation, the study of hyperacute rejection, of delayed xenograft rejection and of accommodation of the graft in xenografting have all contributed to a much greater awareness of how different forms of endothelial activation may affect graft survival. Briscoe, Alexander and Lichtman cover a wide range of T lymphocyte interactions that may potentially contribute to activation, regulation and even downregulation of T cells. As these authors stress, however, the experimental work in this area has largely been done in vitro, leaving enormous uncertainty about which findings are relevant in vivo. While it now appears certain that interactions with donor endothelium are highly significant, it is far from clear how these interactions compare both in importance and in timing to the interactions - - that occur between T cells and antigen-presenting cells of both the donor and recipient in draining lymph nodes.
Natural killer cells Although a role for natural killer (NK) cells in resisting allogeneic bone marrow transplantation has been known for some time, Manilay and Sykes (pp 532-538) describe how much more powerful this resistance is for xenogeneic bone marrow; they review the increasing evidence that NK cells may participate in solid organ rejection in xenogeneic combinations. Fortunately, along with the increasing recognition of the importance of NK cells, there has been
an explosive increase in our knowledge of the biology of these cells - - as Manilay and Sykes discuss in detail. From a transplantation point of view, the key question is how to turn off NK cell function most effectively. Manilay and Sykes describe a number of different potential approaches for this purpose: these include tolerization by bone marrow transplantation; the avoidance of activation signals through either the Fc receptor or the recently described killer activation receptors; and inhibition of activation by engaging the growing number of killer inhibitory receptors that have been identified. T h e last approach has generated particular interest in the field of xenogeneic transplantation since transgenic donors might be generated expressing human M H C class I molecules or their analogs; however, the review by Manilay and Sykes suggests that more than one approach may eventually be required.
Xenotransplantation and retroviral infection T h e last article in this section is specifically about xenotransplantation. Patience, Takeuchi and Weiss (pp 539-542) discuss the infectious risks associated with the use of animal donors. While dozens of other authors have offered their comments on this issue, few have the experience or the credentials of these investigators. Patience, Takeuchi and Weiss indicate that the search for previously unrecognized exogenous viruses in pigs must continue; the authors suggest that the use of nonhuman primates for clinical transplantation is unlikely to be acceptable in the foreseeable future. T h e primary question, however, is how to assess the risk of endogenous retroviruses from pigs becoming pathogenic and infectious in human beings, as a result of xenotransplantation. T h e views expressed by Patience, Takeuchi and Weiss are, to a large extent, those that have formed the basis for the decision of the Food and Drugs Administration in the United States to proceed again with small, carefully supervised clinical trials of xenotransplantation. In essence, the authors argue that the risks of pathogenicity are extremely low and can only be determined finally by human trials. Big questions remain in this area: these include how many xenotransplants, performed safely, will be enough to prove the absence of a risk; and what the regulatory response should be if evidence of transmission of porcine endogenous retroviruses (PERVs) to humans is obtained without evidence of pathogenicity?
Conclusion Together, the articles in this section highlight exciting areas of progress in transplantation immunology; however, in each area the progress has generated even more questions for future investigation.