Skip Navigation LinksHome > March 15, 2014 - Volume 97 - Issue 5 > Increased Soluble CD154 (CD40 Ligand) Levels in Xenograft Re...
doi: 10.1097/TP.0000000000000042
Basic and Experimental Research

Increased Soluble CD154 (CD40 Ligand) Levels in Xenograft Recipients Correlate With the Development of De Novo Anti-Pig IgG Antibodies

Ezzelarab, Mohamed B.1,5; Ekser, Burcin1,2; Isse, Kumiko1; Iwase, Hayato1; Morelli, Adrian E.1,3; Ayares, David4; Cooper, David K.C.1

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Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

© 2014 by Lippincott Williams & Wilkins



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