Renal transplantation has emerged as the treatment of choiCe for pediatric patients with end-stage renal disease (ESRD). This therapy offers the best hope for a near normal life for these Children, including the prospects for normal growth and development. Unfortunately, nearly 30% of pediatric ESRD patients awaiting renal transplantation are considered highly-HLA- sensitized. This results in a significant prolongation of waiting time for transplantation, and often precludes transplantation altogether. Even after transplantation, the highly-HLA-sensitized state results in a higher risk for allograft rejection and loss. There are currently no proven therapies to lower anti-HLA antibody reactivity and enhanced alloimmune responses in these patients. Our hypothesis is that IVIG can modulate humoral and cellular immune reactivity' toward alloantigenic targets, and could be useful in the down regulation of anti-HLA antibody levels and alloimmune responses. Data from our lab and others has established that IVIG inhibits lymphocytotoxicity of anti-HLA class l antibodies in vitro, and lowers levels of anti-HLA antibody in highly-HLA-sensitized individuals. IVIG also strongly inhibits the mixed lymphocyte reaction (MLR) suggesting a possible role for this reagent in inhibition of alloreactivity. Based on these preliminary observations, we propose to conduct a double blinded, block randomized, placebo-controlled trial of IVIG infusion in highly-HLA-sensitized pediatric patients to assess its effectiveness in lowering cytotoxic antibody titers and alloreactivity. The specific objectives of this proposal are: A). To determine if IVIG is more effective than placebo for reduction of cytotoxic anti-HLA antibodies and anti- endothelial cell antibodies (AECA) in highly-HLA-sensitized pediatric ESRD patients. B). To determine if IVIG treatment is more effective than placebo in conferring a long-lasting suppression of anti-HLA antibody levels, AECA levels, and alloreactivity measured by the ability of IgG/lgM isolated from patients' sera to suppress 3rd party MLRs. In addition, we will study the patients MLR reactivity over time toward a constant allogeneically dissimilar target to determine if cellular reactivity is also reduced in IVIG treated vs placebo treated patients. C). To determine if IVIG treated patients, through inhibition of anti-HLA antibody levels receive renal allografts more rapidly than would be anticipated when compared to the placebo treated patients. Data obtained from this study will help us better understand the immunoregulatory mechanisms of IVIG on allospecific immune responses in pediatric ESRD patients, and could result in the establishment of protocols to reduce humoral and cellular alloimmunity with subsequent improvements in transplantation rates and reduced rates of graft rejection. A secondary benefit would be the development of tests that would identify specific antibodies involved in blocking cytotoxicity and reactions. Thus, reagent lots with high-titer blocking antibodies could be identified for use in these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AI037313-04S1
Application #
2879583
Study Section
Special Emphasis Panel (SRC (21))
Project Start
1994-09-30
Project End
2002-08-31
Budget Start
1997-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Toyoda, Mieko; Petrosyan, Anna; Pao, Andy et al. (2004) Immunomodulatory effects of combination of pooled human gammaglobulin and rapamycin on cell proliferation and apoptosis in the mixed lymphocyte reaction. Transplantation 78:1134-8
Jordan, Stanley C; Tyan, Dolly; Stablein, Don et al. (2004) Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol 15:3256-62
Toyoda, Mieko; Pao, Andy; Petrosian, Anna et al. (2003) Pooled human gammaglobulin modulates surface molecule expression and induces apoptosis in human B cells. Am J Transplant 3:156-66
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Toyoda, M; Petrosian, A; Jordan, S C (1999) Immunological characterization of anti-endothelial cell antibodies induced by cytomegalovirus infection. Transplantation 68:1311-8
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Toyoda, M; Carlos, J B; Galera, O A et al. (1997) Correlation of cytomegalovirus DNA levels with response to antiviral therapy in cardiac and renal allograft recipients. Transplantation 63:957-63