Rejection of islets differing by a single antigen is dependent on donor MHC

To study the effect of expression of a single foreign antigen on the outcome of otherwise compatible mouse islet grafts, we have used transgenic mice expressing the human complement receptor 2 (CR2, CD21, C3d/EBV receptor) on their pancreatic beta-cells (RIP-CR2 mice). Donors were RIP-CR2 mice, typed at the major histocompatibility complex (MHC) as H-2(k), H-2(b), or H-2(bxk), and recipients were streptozotocin-treated nontransgenic B6 x CBA F1 mice (H-2(bxk)). H-2(b) or H-2(bxk) CR2-expressing islets were not rejected (mean survival time [MST] >100 days) but induced a peri-insulitis and an antibody response to CR2. In contrast, H-2(k) CR2-expressing islets were rejected in 80% of the cases with a MST of 65 +/- 23 days and were massively infiltrated by a destructive insulitis. In both cases, the infiltrate was mainly made of CD4+ cells, with few CD8+ cells. The isotype of IgG antibody response to CR2 was studied: recipients of H-2(k) grafts had a predominantly IgG1 response, while recipients of H-2(b) grafts had a balanced IgG2a and IgG1 response. To further evaluate the mechanism of differential rejection of the two types of grafts, recipients were immunized with CR2-expressing rat insulinoma cells before transplantation. Preimmunization with CR2 did not affect the outcome of H-2(b) grafts but greatly accelerated the rejection of H-2(k) grafts. These experiments indicate that expression of a single foreign antigen on beta-cells triggers an immune response leading to rejection or to peri-insulitis, depending on the MHC of donor islets.