Regulation of B- and T-cell mediated xenogeneic transplant rejection by interleukin 12.
BACKGROUND
Xenotransplantation may provide a solution to the increasing shortage of donor organs. Acute vascular rejection and cell-mediated rejection remain the primary barriers to successful xenotransplantation. In animal models where acute vascular rejection can be attenuated, xenografts succumb to cell-mediated rejection. The mechanisms of acute vascular rejection and cell-mediated rejection are poorly understood.


METHODS
Using a heterotopic rat-to-mouse cardiac transplantation model, we demonstrate that IL-12p40 attenuates both allogeneic and xenogeneic acute vascular rejection pathology by suppressing B-cell activation and anti-rat isotype switching. To study the mechanism of xenogeneic cell-mediated rejection, we use B-cell deficient mice that only develop cell-mediated rejection pathology. To elucidate the role of IL-12 in cell-mediated rejection, we generated B cell/ IL-12p40 double knockout mice.


RESULTS
We demonstrate that xenogeneic cell-mediated rejection is mediated by CD4+ T cells, and is accompanied by elevated FasL and granzyme mRNA expression. Strikingly, by generating B cell/IL-12p40 double knockout mice, we demonstrate that xenogeneic cell-mediated rejection is IL-12p40 dependent. In contrast, we demonstrate that allogeneic cellular rejection is IL-12p40 independent.


CONCLUSIONS
We conclude that IL-12 plays a dual role in xenotransplantation by driving xenogeneic CD4+ T cell responses but suppressing both allogeneic and xenogeneic B cell responses. Therefore, the mechanism of allogeneic and xenogeneic transplantation rejection is differentially regulated by IL-12.
Hosiawa
Karoline A
KA
Division of Experimental Therapeutics, University Health Network, Toronto General Research Institute, Toronto, Ontario, Canada.
Wang
Hao
H
DeVries
Mark E
ME
Garcia
Bertha
B
Jiang
Jifu
J
Zhou
Dejun
D
Cameron
Mark J
MJ
Zhong
Robert
R
Kelvin
David J
DJ
D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D000910:Antibodies, Heterophile; D018076:DNA, Complementary; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12