Natural Killer T-Cells Participate in Rejection of Islet Allografts in the Liver of Mice

Abstract

A role of natural killer T (NKT) cells in transplant rejection remains unknown. Here, we determined whether NKT cells participate in rejection of islet allografts, using NKT cell-deficient mice. Survival of islet allografts in streptozotocin-induced diabetic CD1d ؊/؊ mice or V␣14 NKT cell ؊/؊ mice was significantly prolonged without immunosuppression when grafted into the liver, but not beneath the kidney capsule, compared with wild-type mice. Acceptance of intrahepatic islet allografts was achieved in CD1d ؊/؊ mice by a subtherapeutic dose of rapamycin, which was abrogated in conjunction with the transfer of hepatic mononuclear cells from wild-type, but not from CD1d ؊/؊ , mice at islet transplantation. The second islet grafts from a donor-specific, but not from a third-party, strain in CD1d ؊/؊ mice bearing functional islet allografts were accepted without immunosuppression at 120 days after the initial transplantation. These findings demonstrate that NKT cells play a significant role in rejection of islet allografts in the liver of mice, but that NKT cells are not essential for induction of donor-specific unresponsiveness in this model. The current study indicates that NKT cells might be considered as a target for intervention to prevent islet allograft rejection when the liver is the site of transplantation. Diabetes 55:34 -39, 2006

Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients

“…These results could be explained by the preferential homing of Th1-inducing iNK T subpopulations towards atheromatous lesions in this particular animal model, as it was reported to be due to interferon (IFN)-g secretion [28]. Also, iNK T cells have been shown to mediate allograft rejection, but without distinction regarding the iNK T subpopulations involved [29]. Interestingly, similar to our results in stable cardiac allograft recipients, a previous study has shown a decreased proportion of circulating iNK T levels as well as of the CD4 + iNK T cell subset in stable renal transplant recipients [30].…”

Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet‐transplantation enhances immediate post‐transplant islet graft function but not long‐term normoglycemia

“…The liver as transplantation side is considered to be a major contributor to these low success rates. Inadequate revascularization,5 the large numbers of natural killer T cells in the liver,6 high concentrations of immunosuppressive drugs,7, 8 and the instant blood‐mediated inflammatory reaction9 play a role in islet graft failure after intraportal transplantation. Therefore, a more adequate transplantation site is required for this technology to gain widespread acceptance and practice.…”

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

“…Sirolimus doses of 2-6 mg/kg/day provided maximum graft survival in the heterotopic heart allograft model, 26 and intraperitoneal doses as high as 24 mg/kg have been used to induce tolerance to skin allograft in mice. 27,28 The tacrolimus dose employed by us (6 mg/kg) was also near or within the range that has been used in experimental models of allograft rejection [29][30][31] or of the injury induced after reperfusion 32 or partial hepatectomy. 33 In addition, some studies suggest that a higher than usual dose of tacrolimus is required for inhibiting the innate cell-mediated immune response, and doses of 10 mg/kg/day have been used in mice for this purpose.…”