Enforced c-REL deficiency prolongs survival of islet allografts1.
BACKGROUND
The NF-kappaB/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-kappaB/Rel family, is essential for transplantation immunity is not known.


METHODS
We explored the role of c-Rel in the anti-allograft 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 wild-type 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.
Yang
Hua
H
Division of Nephrology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
Thomas
Dolca
D
Boffa
Daniel J
DJ
Ding
Ruchuang
R
Li
Baogui
B
Muthukumar
Thangamani
T
Sharma
Vijay K
VK
Lagman
Milagros
M
Luo
Guo-Xiong
GX
Kapur
Sandip
S
Liou
Hsiou-Chi
HC
Hancock
Wayne W
WW
Suthanthiran
Manikkam
M
D000818:Animals; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000276:immunology; D013370:Subrenal Capsule Assay; D014184:Transplantation, Homologous / Q000502:physiology
D016207:Cytokines; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger