Allograft Acceptance Despite Differential Strain-Specific Induction of TGF-β/IL-10-Mediated Immunoregulation

Authors

  • Alice A. Bickerstaff,

    1. The Ohio State University College of Medicine, Departments of aSurgery, bPathology, and Molecular Virology, Immunology, and cMedical Genetics, and the dComprehensive Cancer Center, Columbus, OH 43210, USA
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  • a Jiao-Jing Wang,

    1. The Ohio State University College of Medicine, Departments of aSurgery, bPathology, and Molecular Virology, Immunology, and cMedical Genetics, and the dComprehensive Cancer Center, Columbus, OH 43210, USA
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  • a Dongyuan Xia,

    1. The Ohio State University College of Medicine, Departments of aSurgery, bPathology, and Molecular Virology, Immunology, and cMedical Genetics, and the dComprehensive Cancer Center, Columbus, OH 43210, USA
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  • and a Charles G. Orosz ad

    1. The Ohio State University College of Medicine, Departments of aSurgery, bPathology, and Molecular Virology, Immunology, and cMedical Genetics, and the dComprehensive Cancer Center, Columbus, OH 43210, USA
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*Corresponding author: Alice A. Bickerstaff, bickerstaff-1@medctr.osu.edu

Abstract

We examined the immune approaches that C57BI/6 and BALB/c mice take when treated to accept cardiac allografts. C57Bl/6 mice accept DBA/2 cardiac allografts when treated with gallium nitrate (GN) or anti-CD40L mAb (MR1). These allograft acceptor mice fail to mount donor-reactive delayed type hypersensitivity (DTH) responses, and develop a donor-induced immunoregulatory mechanism that inhibits DTH responses. In contrast, BALB/c mice accept C57BI/6 cardiac allografts when treated with MR1 but not with GN. These allograft acceptor mice display modest donor-reactive DTH responses, and do not develop donor-induced immune regulation of DTH responses. Real-time PCR analysis of rejecting graft tissues demonstrated no strain-related skewing in the production of cytokines mRNAs. In related studies, C57Bl/6 recipients of cytokine and alloantigen educated syngeneic peritoneal exudate cells (PECs) failed to mount DTH responses to the alloantigens unless neutralizing antibodies to transforming growth factor-beta (TGF-β were present at the DTH site demonstrating regulation of cell-mediated alloimmune responses. In contrast, BALB/c recipients of cytokine-and alloantigen-educated PECs expressed strong DTH responses to alloantigens demonstrating a lack of regulated alloimmunity. In conclusion, C57BI/6 mice respond to immunosuppression by accepting cardiac allografts and generating TGF-β-related regulation of donor-reactive T cell responses, unlike BALB/c mice that do not generate these regulatory responses yet still can accept cardiac allografts.

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