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.
