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Indirect Recognition of Porcine Swine Leukocyte Ag Class I Molecules Expressed on Islets by Human CD4⁺ T Lymphocytes¹

Barbara Olack^*, Partha Manna^*, Andrés Jaramillo^*,, Nancy Steward^*, Carol Swanson^*, Dana Kaesberg^*, Nancy Poindexter^*, Todd Howard^* and Thalachallour Mohanakumar^2,*,

Departments of ^* Surgery and Pathology, Washington University School of Medicine, St. Louis, MO 63110

Xenotransplantation of porcine islets is considered a viable alternative treatment for type 1 diabetes mellitus. Therefore, we characterized human PBL responding to porcine islets both in vitro by coculture and in vivo using SCID mice reconstituted with human PBLs (HuPBL-SCID) and transplanted with porcine islets. T cell lines generated in vitro and graft-infiltrating T cells obtained from HuPBL-SCID mice were CD4⁺-proliferated specifically to porcine islets cultured with autologous APC. This proliferation was abrogated by an anti-human class II Ab. These T cell lines also proliferated to purified swine leukocyte Ag (SLA) class I molecules in the presence of self-APC, indicating that the primary xenoantigens recognized are peptides derived from SLA. This CD4⁺ T cell line lysed porcine islets but not splenocytes. CD4⁺ T cell clones with Th0, Th1, and Th2 cytokine profiles were isolated. The Th0 and Th1 clones lysed porcine islets, whereas the Th2 clone that secreted a large amount of IL-4 was not lytic. These results demonstrate that human T cells responding to porcine islets are primarily CD4⁺ and recognize porcine xenoantigens by the indirect Ag pathway presentation. These activated T cells produce cytokines that lyse islets. Furthermore, we demonstrate that the major porcine xenoantigens recognized are SLA class I molecules.

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