Search

The role of the innate immune system in the development of thrombotic microangiopathy (TM) after alpha1,3-galactosyltransferase gene-knockout (GTKO) pig organ transplantation in primates is uncertain.Twelve organs (nine hearts, three kidneys) from GTKO pigs were transplanted into baboons that received no immunosuppressive therapy, partial regimens, or a full regimen based on costimulation blockade. After graft failure, histologic and immunohistologic examinations were carried out.Graft survival of less than 1 day was prolonged to 2 to 12 days with partial regimens (acute humoral xenograft rejection) and to 5 and 8 weeks with the full regimen (TM). Clinical or laboratory features of consumptive coagulopathy occurred in 7 of 12 baboons. Immunohistochemistry demonstrated IgM, IgG, and complement deposition in most cases. Histopathology demonstrated neutrophil and macrophage infiltrates, intravascular fibrin deposition, and platelet aggregation (TM). Grafts showed expression of primate tissue factor (TF), with increased mRNA levels, and TF was also expressed on baboon macrophages/monocytes infiltrating the graft.Our data suggest that (1) irrespective of the presence or absence of the adaptive immune response, early or late xenograft rejection is associated with activation of the innate immune system; and (2) porcine endothelial cell activation and primate TF expression by recipient innate immune cells may both contribute to the development of TM.

An understanding of the mechanisms that suppress the human anti-pig cellular response is key for xenotransplantation. We have compared the ability of human regulatory T cells (Tregs) to suppress xenogeneic and allogeneic responses in vitro.Human peripheral blood mononuclear cells (PBMC), CD4+ T cells, or CD4+ CD25- T cells were stimulated with irradiated human or wild type (WT) or alpha1,3-galactosyltransferase gene-knockout (GT-KO) pig PBMC in the presence or absence of human CD4+ CD25 high Tregs. In separate experiments, 5- (and 6)-carboxyfluorescein diacetate succinimidyl ester-labeled human CD4+ T cells were stimulated with human or pig PBMC. The expansion and precursor frequencies of allo- and xenoreactive Tregs were assessed by labeling with FoxP3 mAb and flow cytometric analysis.The responses of human PBMC, CD4+ T cells, and CD4+ CD25- T cells to pig PBMC were stronger than to human PBMC (P0.05). Human anti-GT-KO responses were weaker than anti-WT responses (P0.05). Human CD4+ CD25 high Tregs suppressed proliferation of CD4+ CD25- T cells to both human and pig PBMC stimulator cells with the same efficiency. Alloreactive CD4+ CD25+ FoxP3 high responder T cells proliferated more than their xenoreactive counterparts (P0.05), although xenoreactive CD4+ CD25+ T cells proliferated more than alloreactive cells (P0.05). There was no difference in precursor frequency between allo- and xeno-reactive CD4+ CD25+ FoxP3 high cells.Human T-cell responses to pig cells are stronger than to allogeneic cells. The human response to GT-KO PBMC is weaker than to WT PBMC. Although human Tregs can suppress both responses, expansion of CD4+ CD25+ FoxP3 high cells against pig PBMC is weaker than against human PBMC. More human Tregs may be required to suppress the stronger xenogeneic response.

Background. Clinically, liver dysfunction in renal transplant recipients is related to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The contribution of parvovirus B19 (B19) to liver disease in renal transplant recipients has not been studied. Here we present the association of liver dysfunction with or without the coinfection of B19, HBV, and HCV after renal transplantation. Methods. We used enzyme-linked immunosorbent assay to identify B19, HBV, and HCV infections in serum samples taken from 144 renal transplant recipients before transplantation and at 12 and 24 months after transplantation. After each patient had fasted for 12 hr, blood was taken for measurement of aspartate aminotransferase and alanine aminotransferase monthly for at least 6 months. Results. Liver dysfunction developed at the significantly higher incidence of 47% in the anti-HCV(+) patients compared with 6% in the noninfected group (P