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Fetal pig islet xenografts in NOD/Lt mice: The effect of peritransplant anti‐CD4 monoclonal antibody and graft immunomodification on graft survival, and lack of expression of Gal(α1–3)Gal on endocrine cells

Abstract: Transplantation of tissues that are vascularized by ingrowth of host vessels, as opposed to primarily vascularized grafts, may be one way of avoiding hyperacute rejection (HAR). Pretransplant treatment of the graft to eliminate from it highly immunogenic cells may also improve graft survival. We examined organ cultured fetal pig pancreas in prediabetic NOD/Lt female mice treated with peritransplant anti‐CD4 MAb (GK 1.5) and in separate experiments also studied the expression of Gal(α 1–3)Gal, an epitope that may be a major target of a human anti‐pig response. Immunocytochemistry to detect insulin, glucagon, and somatostatin and Gal(α 1–3)Gal showed that differentiated (i.e., hormone containing) endocrine cells were Gal(α 1–3)Gal negative but hormone‐negative ductal cells showed strong Gal(α1–3)Gal staining on their luminal border and interstitial cells were also positive particularly early after transplantation. Rejection occurred in all animals, but its rate was markedly altered by transient immunosuppression with the depleting anti‐CD4 MAb. Cell infiltration was first detected in controls 2 days posttransplant, was pronounced by 4 days, and grafts showed advanced rejection by 7 days whether or not they had been “immunomodified” by 2 days exposure to 90% O2. In contrast, peritransplant immunosuppression with GK 1.5 improved graft survival but rejection was advanced by 28 days. The control graft sites had many eosinophils, macrophages and mast cells by 4 days, but little infiltration was seen until after 14 days in the immunosuppressed mice and was predominantly by mononuclear cells. Use of “immunomodified” grafts was of no benefit. Thus, graft immunomodification per se, that often allows islet allografts to survive in rodents, had no effect on xenograft survival in this model. A major potential target antigen for natural Ab in humans, Gal(α 1–3)Gal, is not present on differentiated graft endocrine cells.