Indirect recognition of allo MHC peptides--potential role in human transplantation.

viral peptides), with the main difference that peptides of Introduction allogeneic origin are presented by self antigen presenting cells (APCs) (Figure 1). These peptides are derived from The introduction of cyclosporin in the early 1980s led to donor MHC molecules, presumably after being shed a dramatic improvement of transplant survival rates from the allograft into the recipient’s circulation. The mainly through a reduction of acute rejection episodes molecules are internalized by the recipient’s APCs, proearly after transplantation. The long term decline in graft cessed and presented on the cell surface by self MHC function, however, was not significantly influenced as class II molecules. The T-cells of the recipient are activindicated by a virtually unchanged half life of 7–8 years ated after recognizing this combined structure of a forfor kidney transplants [1]. Thus a main focus of transeign peptide presented in the groove of a self MHC plantation research remains to elucidate the mechanisms molecule [6,7]. In the case of indirect allorecognition the that lead to this perpetual long term loss of kidney activated CD4+T-cells mediate the effector mechanisms allograft function. It is now believed that both immunoof allograft rejection (cell-mediated cytotoxicity, antilogical as well as non-immunological factors ‘injure’ the body-dependent cytotoxicity, delayed-type hypersensitallograft resulting in functional and morphological ivity reactions/inflammation and natural killing) by changes known as chronic allograft failure/rejection [2]. providing the necessary cytokines for the activation of CD8+ T-cells, B-cells, macrophages and natural killer cells (Figure 1). The direct and the indirect pathways of Recent work by several investigators using synthetic, allorecognition MHC derived peptides indicates that this particular way of allorecognition occurs in animals and in humans. The central immunological event that initiates allograft DeKoster et al. [8] were first to show that human T-cells rejection is the recognition of allo-MHC-molecules by recognize processed allo-MHC in a self restricted manner. recipient T-cells [3,4]. The allorecognition process was T-cell clones primed by a HLA-DR3 derived peptide long considered to occur exclusively in a direct fashion, were able to proliferate to allo-MHC (HLA-DR3) molecwhere T-cells recognize intact allo-MHC-molecules on ules on HLA-DR3/DP3 cells. the surface of donor cells. Then, in the early 1980s, Liu and Suciu-Foca [9] studied a larger number of Lechler and Batchelor [5] suggested an additional different synthetic peptides and demonstrated that route of T-cell recognition of alloantigen. They human responder T-cells primed in vitro by allogeneic observed that MHC-incompatible rat kidney allografts, DR1 expressing cells recognize and proliferate to synthetic MHC peptides derived from the hypervariable that were dendritic-cell-depleted after being ‘parked’ domaine of the DRb1*0101 molecule when presented by in intermediate hosts could be rejected in certain donor/ self APCs. Liu’s work brought about another important recipient combinations after retransplantation. observation: the frequency of T-cells taking part in the A decade later major advances in the field of biochemindirect mode of presentation is about 100-fold lower istry, e.g. the discovery of the structure of MHC class I than that of T-cells recognizing the whole MHC molecule and II molecules, new insights into antigen processing directly [10]. This must be kept in mind when one and presentation, and the ability to synthesize peptides interprets results of clinical studies that investigate the corresponding to known sequences of MHC molecules, indirect mode of presentation in humans. provide insights into the mechanisms underlying this second way of allorecognition. The indirect pathway of allorecognition resembles that of nominal antigens (e.g. What is the role for the indirect pathway of allorecognition in transplant recipients? Correspondence and offprint requests to: B. Watschinger, Department of Medicine, Renal Division, University of Vienna, Medical School, Allopeptide specific T-cells can be found in the blood Allgemeines Krankenhaus, Wahringer Gurtel 18–20, A-1090 Wien, Austria. of transplant recipients. Lymphocytes from HLA-A2