Transplantation tolerance: a journey from ignorance to memory.

Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr–/– mice. levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. A, Bottiger C et al. Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. et al. Cuprophane but not synthetic membrane induces increases in serum tumor necrosis factor-alpha levels during hemodialysis. proinflammatory and regulatory monokines in hemodialysis patients shown at a single cell level. Production of interleukin-6, tumor necrosis factor alpha and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients. production of interleukin-10 and inflammatory cytokines in blood monocytes of hemodialysis patients. et al. Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardio-vascular events. 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 alloim-mune 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. 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 …