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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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
Publication statusPublished - 1 Aug 2002
Externally publishedYes

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Allografts
Graft Survival
Immunity
rel Genes
Innate Immunity
Real-Time Polymerase Chain Reaction
Transcription Factors
Transplantation
Immunohistochemistry
Macrophages
Apoptosis
Cytokines
Inflammation
T-Lymphocytes
Transplants
Phenotype
Kidney
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Transplantation

Cite this

Yang, H., Thomas, D., Boffa, D. J., Ding, R., Li, B., Muthukumar, T., ... Suthanthiran, M. (2002). Enforced c-Rel deficiency prolongs survival of islet allografts. Transplantation, 74(3), 291-298.

Enforced c-Rel deficiency prolongs survival of islet allografts. / Yang, Hua; Thomas, Dolca; Boffa, Daniel J.; Ding, Ruchuang; Li, Baogui; Muthukumar, Thangamani; Sharma, Vijay K.; Lagman, Milagros; Luo, Guo Xiong; Kapur, Sandip; Liou, Hsiou Chi; Hancock, Wayne W.; Suthanthiran, Manikkam.

In: Transplantation, Vol. 74, No. 3, 01.08.2002, p. 291-298.

Research output: Contribution to journalArticle

Yang, H, Thomas, D, Boffa, DJ, Ding, R, Li, B, Muthukumar, T, Sharma, VK, Lagman, M, Luo, GX, Kapur, S, Liou, HC, Hancock, WW & Suthanthiran, M 2002, 'Enforced c-Rel deficiency prolongs survival of islet allografts', Transplantation, vol. 74, no. 3, pp. 291-298.
Yang H, Thomas D, Boffa DJ, Ding R, Li B, Muthukumar T et al. Enforced c-Rel deficiency prolongs survival of islet allografts. Transplantation. 2002 Aug 1;74(3):291-298.
Yang, Hua ; Thomas, Dolca ; Boffa, Daniel J. ; Ding, Ruchuang ; Li, Baogui ; Muthukumar, Thangamani ; Sharma, Vijay K. ; Lagman, Milagros ; Luo, Guo Xiong ; Kapur, Sandip ; Liou, Hsiou Chi ; Hancock, Wayne W. ; Suthanthiran, Manikkam. / Enforced c-Rel deficiency prolongs survival of islet allografts. In: Transplantation. 2002 ; Vol. 74, No. 3. pp. 291-298.
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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.",
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T1 - Enforced c-Rel deficiency prolongs survival of islet allografts

AU - Yang, Hua

AU - Thomas, Dolca

AU - Boffa, Daniel J.

AU - Ding, Ruchuang

AU - Li, Baogui

AU - Muthukumar, Thangamani

AU - Sharma, Vijay K.

AU - Lagman, Milagros

AU - Luo, Guo Xiong

AU - Kapur, Sandip

AU - Liou, Hsiou Chi

AU - Hancock, Wayne W.

AU - Suthanthiran, Manikkam

PY - 2002/8/1

Y1 - 2002/8/1

N2 - 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.

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