frequency of human xenoresponding cells to be comparable to those found in allogeneic responses. Indeed, most studies have observed direct responses by CD4+ T cells in vitro that are at least as strong or stronger than allogeneic responses measured under the same conditions. These findings may reflect the high degree of homology between pig and human class II antigens that has been noted previously at the DNA level.

The induction of human anti-pig CD8+ T cell responses in vitro has been documented in several studies. Whereas intact proliferation by purified CD8+ T cells directed against class I xenoantigens has been described, others have observed the proliferation of CD8+ T cells following direct recognition of porcine APC to be dependent on the presence of IL-2 or help from CD+ T cells. This finding would represent a departure from the response of CD8+ T cells under allogeneic conditions. Overall, however, the proliferative responses by CD8+ T cells are less robust when compared to those observed by CD4+ T-cell populations. This serves to underscore the distinct role of CD4+ T cells in the xenogeneic cellular immune response.

The so-called 'two-signal' model of T-cell activation requires appropriate TCR-MHC binding be accompanied by an effective costimulatory signal(s) generated through MHC unrestricted receptor-ligand interactions(s). Examples of second signal receptor-ligand pairs include the interaction between CD28 on T cells and the B7 family of molecules expressed on APCs, as well as CD2-LFA-3 and LFA-1-ICAM interactions. Available data from in vitro studies suggest that several important costimulatory molecule interactions are functionally intact in the pig-to-human species combination. In vitro studies have also shown a vigorous indirect activation of human T cells by autologous APC expressing processed xenoantigens. Indeed, some have suggested that stimulation of human lymphocytes by porcine cells may be independent of MHC expression. An indirect xenogeneic response in excess of that observed for allorecognition may be linked to the greater number of antigenic differences between man and swine, and raises the possibility that the xenogeneic response might be difficult to control using currently available therapies.

The effector phase of allorecognition is characterized by the generation of CD8+ CTLs specific for donor MHC antigen. In vitro studies of cytotoxicity in the human anti-pig response have shown that pig-specific cytotoxic cells can be generated, and that such CTL are MHC restricted. However, the in vitro cytotoxic xenogeneic response is also characterized by a profound nonMHC specific cytotoxic component, which has been linked to NK cells. The cytotoxic effects of NK cells against porcine targets has been shown to be mediated through antibody-dependent and independent mechanisms. Of great interest are recent data indicating that the epitopes recognized NK cells on xenogeneic cells are at least in part the same terminal alpha galactose residues that serve as the target of xenoreactive natural antibodies. It is likely that the marked cytotoxic effects of human NK cells upon porcine cell targets is linked to the failure by NK cell inhibitory receptors (KIRs) to properly interact with pig class I molecules. Transfection of pig cells leading to

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