Kato K, Koyanagi M, Okada H, Takanashi T, Wong YW, Williams AF, Okumura K, Yagita H: CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation

Kato K, Koyanagi M, Okada H, Takanashi T, Wong YW, Williams AF, Okumura K, Yagita H: CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation. J Exp Med 1992; 176: 1241C 1249 [PMC free article] [PubMed] [Google Scholar] 29. lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced AP24534 (Ponatinib) diabetes. CONCLUSIONS This novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted. The potential use of embryonic tissues as a novel source for transplantation, which might be less immunogenic transplantable tissue, has been advocated over the years. AP24534 (Ponatinib) During the past decade, several studies (1C5) have suggested that the relative reduced expression of major histocompatibility complex molecules or adhesion molecules, as well as the lack of antigen-presenting cells or endothelial cells in embryonic tissues, are likely associated with reduced immunogenicity. Furthermore, it has been more recently argued that early embryonic porcine precursor tissues could completely evade the immune system upon implantation into recipient rats or nonhuman primates (NHPs) (6C9). We previously attempted to define an optimal window for transplantation of pig embryonic pancreatic tissue, based on the risk of teratoma, growth potential, and immunogenicity (10,11). Assessment of the first two parameters was performed following implantation of embryonic tissues harvested at different gestational time points under the renal capsule of xenogenic NOD-SCID mice that lack a functional adaptive immune system. To evaluate the relative immunogenicity of the different tissues, the recipient mice were infused with human peripheral blood PIK3R5 mononuclear cells and homing, and destruction of the embryonic tissues by human T-cells or macrophages was analyzed. Based on this study, pig embryonic pancreatic tissue harvested at embryonic gestational age 42 (E42) was selected as the tissue of choice for transplantation. This choice was based, in particular, on the marked growth potential exhibited by E42 tissue, compared with E28 tissue, while no significant difference in their immunogenicity could be detected. Nevertheless, all early embryonic tissues, including tissue harvested at E28, were fiercely rejected when transplanted into immune competent mice in the complete absence of some form of immune suppression. While our findings were in sharp contrast to the studies of Hammerman et al. (6,9), who showed engraftment and normalization of glucose levels in rats transplanted with E28CE29 pig pancreas, it is possible that this discrepancy was due to a difference between rats (used in the Hammerman et al. study) and mice (used in our study) in the strength of their rejection response. Therefore, in the present study, we further tested the potential of E28 pig tissue to evade the immune system in rats. As we previously reported in the mouse model, we observed fierce rejection of the implanted tissue, similar to that exhibited upon transplantation of E42 pancreas. These findings suggest that implantation of embryonic pig pancreas from any gestational stage will likely require some form of immune suppression. Previous transplantation data suggest that costimulatory blockade does not interfere with pancreatic function. Unlike some of the conventional immunosuppressive drugs, such as rapamycin, costimulatory blockade seems preferable for AP24534 (Ponatinib) porcine embryonic pancreas transplantation. One approach, recently demonstrated in the NHP model and also in our previous mouse study, has demonstrated the impressive role of a protocol combining CTLA4-Ig and anti-CD40L (11C13). However, the recent observation that anti-CD40L monoclonal antibody treatment is often associated with lethal thrombotic complications (14) suggests that the use of other costimulatory agents already tested in clinical trials may be preferable. In the present study, we indeed demonstrate that combining anti-LFA1 and anti-CD48 could markedly enhance engraftment and development of E42 pancreatic tissue in immune competent mice. RESEARCH DESIGN AND METHODS Animals. Animals were maintained under conditions approved by the institutional animal care and use committee at the Weizmann Institute of Science. NOD-SCID and AP24534 (Ponatinib) C57BL mice and Nude and Lewis rats aged 8C12 weeks (Weizmann Institute Animal Breeding Center, Rehovot, Israel) were used as hosts for the transplantation studies. Porcine embryonic pancreatic tissue. Pig embryos AP24534 (Ponatinib) were obtained from the Lahav Institute of Animal Research (Kibbutz Lahav, Israel) as previously described (10,11). Cold ischemia time until transplantation.