Antibody-mediated xenograft rejection is associated with vigorous IL-4 production in vivo
Introduction The immunologic basis for why xenografts are rejected by the humoral responses while allografts are rejected by cellular responses is not known. We hypothesize that differential induction of TH1 vs. TH2 responses may be the underlying cause for humoral rejection of xenografts and cellular rejection for allografts. We have tested this hypothesis by quantifying TH1 responses by γ-IFN production and TH2 responses in vivo following xeno or allograft transplantation. We used the newly developed Cincinnati Cytokine Capture Assay (CCCA) to serially measure IL-4 and γ-IFN production in vivo following xeno- or allo-graft transplantation.
Materials and methods Two groups of 10 C57BL/6 mice received heterotopic cardiac xeno (Lewis rat) or allograft (Balb/c). These mice were injected with biotin-labeled anti-IL-4 and anti-γ-IFN mAbs on the indicated post-transplantation days until the mice rejected their transplants. 24 h later the mice were bled, their serum was collected, and the antibody-cytokine complex was measured using the CCCA.
Results There was no difference in the kinetics of the γ-IFN following xeno or allo-transplantation. γ-IFN levels peaked on post-transplant day 3 and returned to baseline by day 6-7. In contrast, there was a dramatic difference in the ability of xeno and allografts to elicit IL-4 production (see Figures). Following xeno-transplantation, IL-4 production peaked earlier (day 3) than the allograft (day 4). In addition, the level of IL-4 in the xenografts was 9 fold greater than the allografts.
Conclusion Our observations support our hypothesis that xenografts are rejected by antibody-mediated mechanisms because of their preferential ability to elicit vigorous IL-4 production. Why xenografts are able to preferentially increase IL-4 production and how IL-4 affects xeno-antibody production is currently being investigated using IL-4 and γ-IFN deficient mice.