1) A major problem in immunology is understanding the nature of the maternal-fetal relationship. Why aren?t fetuses with their paternal alloantigens rejected? We found that maternal lymphocyte and macrophage activities were inhibited in the placenta, which is the interface between mother and fetus. Docosahexaenoic acid (DHA) is present at high concentrations in the placenta and fetus. We found that DHA inhibits macrophage activation by interferon gamma as assessed by the increased expression of Class II MHC and activation of the gene for inducible nitric oxide synthase (iNOS). We are now studying the effect of DHA on activation of the IRF1 and NF kappa B DNA response elements in the promoter region of the iNOS gene.
2) We are testing the hypothesis that kidney transplant rejection requires two major signals. The idea is that the immune system evolved to attack foreign antigens, which injure tissue. Ordinarily the foreign antigen is a pathogen, which injures tissue during infection. During transplant, we propose that the foreign antigen is the allograft, and the injury signal results from damage to the tissue during the transplant surgery. We have performed transplants between inbred strains of rats where there is no rejection. None-the-less the injury from the surgery resulted in the recruitment of dendritic cells into the transplant and the new expression of adhesion molecules and MHC Class II molecules on parenchymal tissues. In other studies, we find that in vitro models of ischemia reperfusion injury cause renal tubule cell lines to express chemokine and cytokine genes which might be important in initiating rejection.
3) We are also investigating the idea that nitric oxide produced during an immune response acts as a feedback inhibitor of macrophage activation. We find that nitric oxide inhibits gene expression of CIITA (Class II Transactivator) and are investigating the effects of this inhibition on Class II MHC, Ii, and DM - genes important in antigen-processing and presentation via the exogenous pathway.
RESEARCH INTERESTS
Acute renal failure
Renal transplant rejection
Perinatal infections and tolerance
RECENT PUBLICATIONS
Kielar,M.L., Jeyarajah,D.R., Lu,C.Y., "The regulation of ischemic acute renal failure by extrarenal organs" Curr. Opin. Nephrol. Hypertension, 11:451-457, 2002
Hariharan,S., Pirsch,J.D., Lu,C.Y., Chan,L., Pesavento,T.E., Alexander,S., Bumgardner,G.L., Baasadona,G., Hricik,D.E., Pescovitz,M.D. et al., "Pancreas after kidney transplantation." J. Am. Soc. Nephrol., 13:1109-1118, 2002
Lu, C.Y., Vazquez, M.A., Kielar, M.L., Jeyarajah,D.R. and Zhou,X.J., "Renal Transplantation" Kelley's Textbook of Internal Medicine, 1297-1303, 2000
Lu,C.Y.; Penfield,J.G.;Kielar,M.L.; Vazquez, M.A.; Jeyarajah,D.R., "Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process?" Kidney International, 55:2157-2168, 1999
Vazquez,M.A., Jeyarahah,D.R., Kielar, M.L., and Lu, C.Y., "Long-term outcomes of renal transplantation: a result of the original endowment of the donor kidney and the inflammatory response to both alloantigens and injury" Curr. Opinion Nephrology and Hypertension, 9:643-648, 2000
SIGNIFICANT PUBLICATIONS
Lu, C.Y., Calamai, E.G. and Unanue, E.R., "A defect in the antigen-presenting function of macrophages from neonatal mice." Nature, 282:327-329, 1979
Khair-El-Din, T.A., Sicher,S.C., Vazquez,M.A., Chung, G.W., Stallworth,K.L. Kitamura,K., Miller,R.T., Lu, C.Y., "Transcription of the murine iNOS gene is inhibited by docosahexaenoic acid, a major constituent of fetal and neonatal sera as well as fish oils" J. Exp. Med., 183:1241-1246, 1996
Redline, R.W. and Lu, C.Y., "The role of local immunosuppression in murine fetoplacental listeriosis." J. Clin. Invest., 79:1234-1241, 1987
Kielar,M.L.; Jeyarajah,D.R.; Zhou,X.J.;Lu, C.Y., "Docosahexaenoic acid ameliorates murine ischemic acute renal failure and prevents increases in mRNA abundance for both TNF alpha and inducible nitric oxide synthase" J. Am. Soc. Nephrol., 14:389-96, 2003
Penfield, J.G., Y.Wang, S. Li, M.A. Kielar, S.C. Sicher, D.R. Jeyarajah, and Lu, C.Y., "Injury from transplant surgery recruits recipient MHC Class II-positive leukocytes, including dendritic cells, into the transplanted kidney in a rat model where there is no rejection." Kidney International, 56:1759-1769, 1999
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