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Timestamp: 2019-04-18 20:50:55+00:00

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This chapter centers on adaptive or antigen-specific cellular responses to xenografts. It emphasizes the nature of T-lymphocyte-dependent immunity to xenografts. Most of the concepts concerning T-cell responses to xenografts developed in the chapter are derived from rodent studies. When considering the T-lymphocyte response to non-self antigens, including xenografts, it is imperative to emphasize the two fundamental properties of T-cell reactions. Although transferred human cells can mediate the rejection of human allografts or porcine xenografts in these animals, they generally fail to initiate vigorous GVHD against the scid mouse host itself. This model of donor MHC-restricted (direct) and host MHC-restricted (indirect) pathways of graft antigen presentation has important implications for the nature of T-cell-dependent immune responses to both allografts and xenografts. Two differing pathways of graft antigen presentation can be envisioned that would fulfill the two-signal requirement for T-cell activation, each involving APC-dependent processes: (i) donor MHC-restricted responses, and (ii) host MHC-restricted responses. CD4-dependent xenograft rejection depends on host and not on donor MHC class II expression. We find that CD4 T cells trigger rapid rejection of rat islet xenografts established in immunodeficient recombinase-activating gene (rag)-deficient hosts. Immunodeficient scid and rag-deficient mice accept tissue and organ xenografts despite retaining innate immune reactivity, including NK-cell function. The precise molecular mechanisms of cellular xenograft rejection remain to be identified, especially regarding the role of particular Th1 and Th2 cytokines in triggering tissue injury.
Direct and indirect pathways of graft antigen presentation. Optimal T-lymphocyte activation requires T-cell receptor recognition of processed peptide antigens complexed with MHC molecules plus appropriate secondary costimulatory signals provided by the antigen-presenting cell (APC). Four potential scenarios are depicted whereby CD4 or CD8 T cells can be activated in response to graft-derived antigens: (1) Direct (donor MHC-restricted) CD4 T-cell activation. In this case, the donor-type APC directly presents its own repertoire of peptides associated with MHC class II molecules to specific CD4 T cells. (2) Direct CD8 T-cell activation. Donor APCs directly present MHC class I/peptide complexes to host CD8 T cells. Note that the high alloreactive precursor frequency is attributed largely to the direct CD4 and CD8 T-cell pathways. (3) Indirect (host MHC-restricted) CD8 T-cell activation. In this case, antigens (generically termed “X”) derived from donor cells are processed and re-presented in association with MHC class I molecules on host-type APC. This pathway, also referred to as “cross-priming,” represents cases in which exogenous antigens enter the MHC class I processing pathway. Although largely disregarded in the past, this pathway may prove to be of greater biological significance than previously considered. (4) Indirect CD4 T-cell activation. This is probably the predominant pathway of responses to most foreign antigens. In this case, graft-derived antigens (“X”) are acquired by host-type APCs and re-presented in association with MHC class II molecules. It is generally accepted that exogenous antigens primarily gain access to the MHC class II processing pathway and so primarily induce CD4 T-cell activation.
Potential T-cell-dependent pathways of graft destruction. CD4 T cells are considered to be major participants in triggering antigen-specific responses to xenografts (see text). CD4 T cells can respond either directly to donor-type APCs or indirectly to graft-derived antigens presented by host APCs. Both of these responses themselves may participate in tissue injury. Direct CD4 T cells would be capable of TCR engagement of MHC class II antigens expressed by donor APCs and vascular endothelium. Indirect CD4 T cells would interact with graft antigens presented by autologous APCs, possibly producing local inflammatory tissue damage. Alternatively, CD4 T cells may collaborate with other lymphocyte subpopulations that can participate in graft rejection. On one hand, the “direct” type CD4 T cell has been chiefly implicated as helping to activate CD8 lymphocytes, leading to a graft-specific cytotoxic T-cell (CTL) response. Alternatively, “indirect” CD4 T cells are the key helper cells for B cells presenting graft-derived antigens, resulting in a graft-specific antibody response.
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