Christopher Lu, M.D.
Professor of Internal Medicine
Medical Director, Renal Transplantation

Research Interests:

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.

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.

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.

Selected Publications:

Jeyarajah DR, Kielar ML, Zhou XJ, Zhang Y, Lu CY. Acute bile duct ligation ameliorates ischemic renal failure. Nephron Physiol. 2003;95(2):p28-35.

Jeyarajah DR, Kielar ML, Frantz N, Lindberg G, Lu CY. Infection by gram-negative organisms via the biliary route results in greater mortality than portal venous infection. Clin Diagn Lab Immunol. 2003 Jul;10(4):664-9.

Kielar ML, Jeyarajah DR, Zhou XJ, Lu CY. 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. 2003 Feb;14(2):389-96.

Kielar ML, Rohan Jeyarajah D, Lu CY. The regulation of ischemic acute renal failure by extrarenal organs. Curr Opin Nephrol Hypertens. 2002 Jul;11(4):451-7.

Vazquez MA, Jeyarajah DR, Kielar ML, Lu CY. 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 Opin Nephrol Hypertens. 2000 Nov;9(6):643-8. Review.

Kielar ML, Sicher SC, Penfield JG, Jeyarajah DR, Lu CY. Nitric oxide inhibits INFgamma-induced increases in CIITA mRNA abundance and activation of CIITA dependent genes--class II MHC, Ii and H-2M. Class II TransActivator. Inflammation. 2000 Oct;24(5):431-45.

Kielar ML, Jeyarajah DR, Penfield JG, Lu CY. Docosahexaenoic acid decreases IRF-1 mRNA and thus inhibits activation of both the IRF-E and NFkappa d response elements of the iNOS promoter. Transplantation. 2000 May 27;69(10):2131-7.

Penfield JG, Dawidson IA, Ar'Rajab A, Kielar MA, Jeyarajah DR, Lu CY. Syngeneic renal transplantation increases the number of renal dendritic cells in the rat. Transpl Immunol. 1999 Dec;7(4):197-200.

Penfield JG, Wang Y, Li S, Kielar MA, Sicher SC, Jeyarajah DR, Lu CY. Transplant surgery injury recruits recipient MHC class II-positive leukocytes into the kidney. Kidney Int. 1999 Nov;56(5):1759-69.

Jeyarajah DR, Kielar M, Penfield J, Lu CY. Docosahexaenoic acid, a component of fish oil, inhibits nitric oxide production in vitro. J Surg Res. 1999 May 15;83(2):147-50.

Lu CY, Penfield JG, Khair-el-Din TA, Sicher SC, Kielar ML, Vazquez MA, Che L. Docosahexaenoic acid, a constituent of fetal and neonatal serum, inhibits nitric oxide production by murine macrophages stimulated by IFN gamma plus LPS, or by IFN gamma plus Listeria monocytogenes. J Reprod Immunol. 1998 Apr;38(1):31-53.

Vazquez MA, Sicher SC, Proctor ML, Crowley JC, Lu CY. Differential regulation of Ia expression and antigen presentation by listeriolysin-producing versus non-producing strains of Listeria monocytogenes. J Leukoc Biol. 1996 May;59(5):683-90.