The goal of this project is to develop a model of immune complex (IC) mediated glomerulonephritis (GN) in the nonhuman primate. The ultimate goal is to use this model to study the pathophysiology of GN in the primates. The impetus to study GN in the primate is provided by the recent evidence, from our laboratory and from other laboratories, that the pathogenesis of IC-mediated disease in the primate may be radically different from that of nonprimates in at least one important respect: Primates possess massive numbers of complement receptor Type 1 (CR1) in the circulation, almost all of which represent CR1 expressed on erythrocytes. This erythrocyte-CR1 """"""""system"""""""" appears to be the key component of an IC clearing mechanism and an IC processing mechanism. Although the existing data suggest strongly that erythrocyte CR1 may be important in IC-mediated disease, all of the evidence is indirect. Thus, the hypothesis has not been tested critically. We suggest that a critical testing of the erythrocyte-CR1 hypothesis is needed because, if erythrocyte CR1 is found to be important in the pathogenesis of GN in the primate, a clear understanding of the role of erythrocyte CR1 in GN could lead to new approaches to the diagnosis and treatment of IC-mediated disease in man. In order to test critically the erythrocyte CR1 hypothesis, it is necessary to have a model of IC-mediated disease in the primate, which can be manipulated. Clearly, such studies must be reserved for the nonhuman primate. We have already undertaken pilot studies in 4 monkeys (2 baboons and 2 cynomolgous) to explore the feasibility of developing a model of IC-mediated disease. Thus far, the results indicate that our goal is entirely feasible. However, given the cost of acquisition and maintenance, the special issues involved in handing nonhuman primates, and the need to examine several different approaches, it is clear that full development of an efficient model will be a relatively large undertaking. This proposal describes the steps that are necessary to develop the model to the point where intervention trails will then be feasible. The intervention trails, which will involve deliberate manipulation of erythrocyte-CR1 number/function during the induction and/or maintenance of IC-mediated disease, will be the subject of a future proposal.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025404-07
Application #
3338055
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1979-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Hebert, L A; Birmingham, D J; Mahan, J D et al. (1997) Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate. Am J Kidney Dis 30:243-52
Hebert, L A; Betts, J A; Sedmak, D D et al. (1996) Loin pain-hematuria syndrome associated with thin glomerular basement membrane disease and hemorrhage into renal tubules. Kidney Int 49:168-73
Hebert, L A; Birmingham, D J; Dillon, J J et al. (1994) Erythropoietin therapy in humans increases erythrocyte expression of complement receptor type 1 (CD35). J Am Soc Nephrol 4:1786-91
Hebert, L A; Birmingham, D J; Mahan, J D et al. (1994) Effect of chronically increased erythrocyte complement receptors on immune complex nephritis. Kidney Int 45:493-9
Hebert, L A; Birmingham, D J; Shen, X P et al. (1994) Rate of antigen entry into the circulation in experimental versus naturally occurring immune complex glomerulonephritis. J Am Soc Nephrol 5:S70-5
Birmingham, D J; Shen, X P; Hourcade, D et al. (1994) Primary sequence of an alternatively spliced form of CR1. Candidate for the 75,000 M(r) complement receptor expressed on chimpanzee erythrocytes. J Immunol 153:691-700
Hebert, L A; Birmingham, D J; Shen, X P et al. (1994) Effect of recombinant erythropoietin therapy on autoimmunity in systemic lupus erythematosus. Am J Kidney Dis 24:25-32
Mahan, J D; Hebert, L A; McAllister, C et al. (1993) Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate. Kidney Int 44:716-25
Hebert, L A; Birmingham, D J; Shen, X P et al. (1992) Stimulating erythropoiesis increases complement receptor expression on primate erythrocytes. Clin Immunol Immunopathol 62:301-6
Hebert, L A; Cosio, F G; Birmingham, D J (1992) The role of the complement system in renal injury. Semin Nephrol 12:408-27

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