Enforced c-Rel deficiency prolongs survival of islet allografts

Hua Yang, Dolca Thomas, Daniel J. Boffa, Ruchuang Ding, Baogui Li, Thangamani Muthukumar, Vijay K. Sharma, Milagros Lagman, Guo Xiong Luo, Sandip Kapur, Hsiou Chi Liou, Wayne W. Hancock, Manikkam Suthanthiran

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Abstract

Background. The NF-κB/Rel family of transcription factors regulates biologic processes ranging from apoptosis to inflammation and innate immunity. Whether c-Rel, a lymphoid-predominant member of the NF-κB/Rel family, is essential for transplantation immunity is not known. Methods. We explored the role of c-Rel in the antiallograft repertory using mice with targeted disruption of the c-Rel gene (c-Rel-/-) as recipients of H-2 mismatched islet allografts. Allogeneic DBA/2 (H-2d) islets were transplanted into the renal subcapsular space of diabetic c-Rel-/- C57BL/6 (H-2b) mice or the c-Rel +/+ C57BL/6 wild-type mice. Islet graft survival, cellular traffic into the islet grafts and their phenotype, and intragraft expression of cytokines and cytotoxic attack molecules were determined at the protein (by immunohistochemistry) and mRNA (by real-time quantitative polymerase chain reaction) levels. Results. We found superior islet graft survival in the c-Rel-/- recipients compared to c-Rel+/+ C57BL/6 recipients. Splenocytes from c-Rel-/- mice proliferated poorly compared to splenocytes from the c-Rel+/+ mice on stimulation with anti-CD3 mAbs or Con A. Peri-islet infiltration composed of T lymphocytes and macrophages was found in both c-Rel+/+ recipients and c-Rel-/- recipients, but intra-islet infiltration was observed only in c-Rel+/+ recipients. Immunohistologic and molecular studies showed impaired T helper-type 1 immunity and decreased intragraft expression of cytotoxic attack molecules perforin and granzyme B in c-Rel-/- recipients as compared to wildtype recipients. Conclusions. Our results demonstrate that c-Rel is essential for robust rejection of islet allografts and support the idea that strategies that impair c-Rel function may be of value for constraining alloimmunity and facilitating survival of allogafts.

Original languageEnglish
Pages (from-to)291-298
Number of pages8
JournalTransplantation
Volume74
Issue number3
DOIs
Publication statusPublished - Aug 2002

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ASJC Scopus subject areas

  • Transplantation

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Yang, H., Thomas, D., Boffa, D. J., Ding, R., Li, B., Muthukumar, T., Sharma, V. K., Lagman, M., Luo, G. X., Kapur, S., Liou, H. C., Hancock, W. W., & Suthanthiran, M. (2002). Enforced c-Rel deficiency prolongs survival of islet allografts. Transplantation, 74(3), 291-298. https://doi.org/10.1097/00007890-200208150-00002