Children or adults with severe congenital T cell defects have abnormalities of in T cell activation in vitro responsive to added IL-2. Since IL-2 can substantially boost T cell function in vitro, a clinical trial was recently conducted to determine if IL-2 could improve T cell functions and the clinical state of infants with SCID phenotype. For 5 of 6 patients, remarkable clinical and immunologic benefit was observed. Since many patients with common variable immunodeficiency have reduced IL-2 production and substantial T cell defects which correctable in vitro by the addition of IL-2, we have established a new collaborative clinical trial with Cetus Corporation to provide us with a new biologic, a recombinant IL-2 conjugated to polyethylene glycol; this coupling procedure results in an IL-2 compound with greatly increased half-life and no loss of biologic activity. In the Cetus protocol we will treat 3 -> 4 pediatric patients with severe T cell defects and 10 - 12 adult and pediatric patients with common variable immunodeficiency (CVI) with T cell defects all of whom will be pre-tested for evidence of an in vitro response to PEG-IL-2. The Cetus protocol includes analyses of clinical state, basic laboratory tests, immunoglobulin and complement levels, enumeration of T and B cell numbers, lymphocyte proliferative responses to mitogens, antigens, allogeneic cells, evaluation of IL-2 production, soluble IL-2 receptors, and skin test reactivity over a 12 week period. What the Cetus protocol does not address is whether B cell activation and differentiation to immunoglobulin production can be detected after PEG-IL-2 treatment and if cytokines other than IL-2 can be produced by T lymphocytes of treated patients. We have recently demonstrated, in two independent systems, that the concept of an irrevocable intrinsic B cell defect to explain the hypogammaglobulinemia in patients with common variable CVI is probably not valid. Our data suggest that, given the appropriate stimulus form T cells, B cells from these patients can secrete immunoglobulin in vitro at normal or near normal levels. Thus, the Ig deficiency may result from improper """"""""communication"""""""" between CVI T cells and autologous B cells. The purpose of this application is to determine whether improved T cell immunity is linked in vitro and/or in vivo to B cell function in these two patient populations. Thus, the purpose of this application is two fold: 1) we will determine if improved T cell proliferation after IL-2 treatment is linked in vitro to enhanced B cell function and 2) if lymphokine secretion by T cells and monocytes in vitro is altered by this treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Mount Sinai School of Medicine
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New York
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Cunningham-Rundles, C; Murray, H W; Smith, J P (1999) Treatment of idiopathic CD4 T lymphocytopenia with IL-2. Clin Exp Immunol 116:322-5
Zhou, Z; Huang, R; Danon, M et al. (1998) IL-10 production in common variable immunodeficiency. Clin Immunol Immunopathol 86:298-304
Branda, R F; Moore, A L; Hong, R et al. (1996) B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1. Clin Immunol Immunopathol 79:115-21
Cunningham-Rundles, C; Kazbay, K; Zhou, Z et al. (1995) Immunologic effects of low-dose polyethylene glycol-conjugated recombinant human interleukin-2 in common variable immunodeficiency. J Interferon Cytokine Res 15:269-76
Cunningham-Rundles, C; Kazbay, K; Hassett, J et al. (1994) Brief report: enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2. N Engl J Med 331:918-21
Cunningham-Rundles, C; Mayer, L; Sapira, E et al. (1992) Restoration of immunoglobulin secretion in vitro in common variable immunodeficiency by in vivo treatment with polyethylene glycol-conjugated human recombinant interleukin-2. Clin Immunol Immunopathol 64:46-56