Ezzelarab MB1, Ekser B, Isse K, Iwase H, Morelli AE, Ayares D, Cooper DK. (2014) Increased soluble CD154 (CD40 ligand) levels in xenograft recipients correlate with the development of de novo anti-pig IgG antibodies. Transplantation. 97(5):502-8. PMID: 244879395
De novo anti-pig antibodies are associated with acute humoral xenograft rejection. We explored the relative efficacy of CD40/CD154-pathway blockade versus CD28/B7-pathway blockade in the prevention of de novo anti-pig IgG antibodies in xenograft recipients.
After α1,3-galactosyltransferase gene-knockout pig artery patch xenotransplantation, recipient baboons received no immunosuppression (IS; n=3), or anti-CD154mAb-based (n=5) or CTLA4-Ig-based (n=5) IS. CD4 T-cell and CD20 B-cell numbers in blood were determined. Serum anti-pig IgG antibodies and serum soluble (s)CD154 levels were measured. In lymph nodes, germinal center formation was examined and numbers of proliferating cells were evaluated by Ki-67 staining.
After transplantation, with no IS, CD4 T-cell and CD20 B-cell numbers were increased, but were reduced by IS.In lymph nodes, with no IS, there was enhanced germinal center formation, which was significantly reduced by anti-CD154mAb-based (P<0.01) or CTLA4-Ig-based (P<0.01) IS. With no IS, there was strong expression of Ki-67-positive cells in lymph nodes, indicating extensive cellular proliferation. Ki-67-positive cells were significantly reduced by anti-CD154mAb-based (P<0.05) but not by CTLA4-Ig-based IS. High mean levels of sCD154 were detected with no IS (3324 pg/mL), in comparison to naive control baboons (214 pg/mL). With anti-CD154mAb-based IS, sCD154 was reduced to less than 1 pg/mL and with CTLA4-Ig-based IS to 65 pg/mL. There was significant positive correlation between sCD154 and anti-pig IgG levels (P<0.01).
In xenograft recipients, anti-CD154mAb may reduce class-switching of anti-pig antibodies by binding both T-cell surface CD154 and circulating sCD154, thus preventing subsequent stimulation of B cells and activation of lymphoid follicles in secondary lymphoid tissues.
Link to journal: http://journals.lww.com/transplantjournal/Pages/default.aspx