Transplant: immunology and treatment of rejection Connie L Davis, MD  American Journal of Kidney Diseases  Volume 43, Issue 6, Pages 1116-1134 (June 2004) DOI: 10.1053/j.ajkd.2004.04.003 Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 1 (a) Direct and indirect recognition of alloantigens. (A) Direct alloantigen recognition occurs when T cells bind directly to intact allogeneic MHC molecules in professional APCs in a graft, as illustrated. (B) Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs, and peptide fragments of the allogenic MHC molecules are presented by recipient (self) MHC molecules. Recipient APCs may also process and present graft proteins other than allogeneic MHC molecules. (b) Recognition of allogeneic MCH molecules by T lymphocytes. Recognition of allogeneic MHC molecules may be thought of as a cross reaction in which a T cell specific for a self MHC molecule-foreign peptide complex (A) also recognizes an allogeneic MHC molecule whose structure resembles that of a self MHC molecule-foreign peptide complex (B and C). Peptides derived from the graft (labeled “donor peptides”) may not contribute to allorecognition (B), or they may form part of the complex that the T cell sees (C). The type of T cell recognition depicted in (B) and (C) is called direct allorecognition. Reproduced with permission from Abbas and Lichtman.1 American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 2 Classes of lymphocytes. Different classes of lymphocytes recognize distinct types of antigens and differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell surface antigens and differentiate into antibody-secreting cells. Helper T lymphocytes recognize antigens on the surfaces of APCs and secrete cytokines, which simulate different mechanisms of immunity and inflammation. Cytolytic T lymphocytes recognize antigens on infected cells and kill these cells. (Note that lymphocytes recognize peptides that are displayed by MHC molecules.) Natural killer cells recognize changes on the surface of infected cells and kill these cells. It should be emphasized that native T cells (CD4 or CD8) are activated by professional APCs. Effector CD8 T cells, not native T cells, can kill and infected cell expressing the specific peptide-class I complex. Reproduced with permission from Abbas and Lichtman.1 American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 3 (a) The structure of class I MCH and class II MHC molecules. The schematic diagrams and models of the crystal structures of class I MHC and class II MHC molecules illustrate the domains of the molecules and the fundamental similarities between them. Both types of MHC molecules contain peptide-binding clefts and invariant portions that bind CD8 (the α3 domain of class I) or CD4 (the β4 domain of class II). β2m, β2 microglobulin. (Crystal structures courtesy of Dr P. Bjorkman, California Institute of Technology, Pasadena, CA.) Reproduced with permission from Abbas and Lichtman.1 (b) A top view of the crystalline structure of an HLA molecule with a peptide in the cleft. (Figure courtesy of Dr Karen Nelson.) American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 4 Mechanisms of killing of infected cells by CD8+ CTLs. CTLs recognize class I MHC-associated peptides of cytoplasmic microbes in infected cells and form tight adhesions (“conjugates”) with these cells. Adhesion molecules, such as integrins, stabilize the binding of the CTLs to infected cells (not shown). The CTLs are activated to release (“exocytose”) their granule contents toward the infected cell (referred to as “targets” of CTL killing). The granule contents include perforin, which forms pores in the target cell membrane and granzymes, which enter the target cell through these pores (or by receptor-mediated endocytosis) and induce apoptosis. Reproduced with permission from Abbas and Lichtman.1 American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 5 The role of costimulation in T-cell activation. Resting APCs, which have not been exposed to microbes or adjuvants, may present peptide antigens but they do not express costimulators and are unable to activate naive T cells. Naive T cells that have recognized antigen without costimulation may become unresponsive to subsequent exposure to antigen, even if costimulators are present and this state of unresponsiveness is called anergy. Microbes, and cytokines produced during innate immune responses to microbes, induce the expression of costimulators, such as B7 molecules, on the APCs. The B7 costimulators are recognized by the CD28 receptor on naive T cells, providing “signal 2,” and in conjunction with antigen recognition (“signal 1”), this recognition initiates T-cell responses. Reproduced with permission from Abbas and Lichtman.1 American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 6 The sensitivity (level of anti-HLA antibody detected) of the various crossmatch assays from the least (Complement-Dependent Cytotoxicity) to the most sensitive (Flow Crossmatch). (Figure courtesy of Dr Karen Nelson.) American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 7 The method for performing the complement-dependent crossmatch. American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 8 The method for performing the antihuman globulin complement-dependent crossmatch. American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 9 (a) The principle of the flow crossmatch. Donor cells are incubated first with recipient serum, then with fluorescent dye-tagged, antihuman globulin, and finally placed into the flow cytometer. As the cells flow through the cytometer, a laser crosses the path and if cells are coated with antihuman antibody a light is emitted from the fluorscent dye and recorded. The total number of emissions recorded can be translated into a relative amount of anti-donor antibody present in the recipient serum. (Figure courtesy of Dr Jar How Lee.) (b) The procedure for the performance of the flow crossmatch. (Figure courtesy of Dr Karen Nelson.) American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 10 (a) The procedure for generating single HLA antigens. Once produced they are placed onto beads for use in the detection of antibodies against specific HLA antigens. (b) The detection of alloantibody by HLA antigen-coated beads. (Figure courtesy of Dr Jar How Lee.) American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 11 The pictoral representation of the major classes of rejection. Reproduced with permission from Abbas and Lichtman.1 American Journal of Kidney Diseases 2004 43, 1116-1134DOI: (10.1053/j.ajkd.2004.04.003) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions