Logical approach to transplant patient monitoring

Abstract

ACUTE and chronic graft rejections as well as tolerance are a true representation of the specificity, complexity, sophistication, and redundancy of an elegantly and meticulously designed immune system. Tolerance is in a way similar to the process of self-recognition where lymphoid clones, baring a self-reactive receptor, are eliminated during development or rendered inactive by “clonal deletion” leading to a state of accommodation and acceptance (anergy). On the other hand, both acute and chronic rejections are manifestations of the very reason of existence of the immune system, which is to defend the host against foreign invaders. Thus, to predict, diagnose, and treat graft rejection it is necessary to determine, and understand the steps leading to recognition, stimulation, activation, and amplification of the immune response. It is generally accepted that the first steps leading to the initiation of the immune system cascade, leading to graft rejection, is recognition. It can be direct, where donor antigens of the major histocompatibility complex (MHC) expressed on the donor cells (passenger leukocytes) or tissues are recognized by the host immune system. There seems to be a general consensus that the direct recognition pathway initiates acute graft rejection. Alternatively, processed donor MHC peptides presented by the recipient antigen presenting cells (APC) initiate the indirect pathway of immune response. Recent studies have shown that the indirect pathway may be as important as the direct, especially in chronic rejection. Although the steps involved in this process are interlocked with each other, the type and strength of the response depends on the host and the nature of the stimulus. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to proceed additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD8/ HLA class I antigens are required. During the activation process, the lymphocyte, begins to acquire new CD molecules such as CD25 (IL-2R), CD69, CD71, and HLA-DR. This is accompanied by an increase of cytokines production by the primed T cell. The cytokines are essential for the differentiation, proliferation, and amplification of the T cell. Response to the most important of these cytokines is IL-2, which is essential for activated T-cell proliferation. The complexity and the polymorphic nature of the immune system has necessitated to design agents that inhibit the immune system at different levels.