Several investigators have now hypothesized that chronic activation of B cells by cytokines in individuals with HIV is in part, the basis for the increased incidence of genetic mutations which are associated with the malignant transformation of B cells and ultimately the development of AIDS lymphoma. Proof of this is lacking, and the characterization of factors which may be responsible for chronic B cell activation in HIV and AIDS is presently incomplete. We are currently engrafting human lymphocytes (hu-PBL) into mice with severe combined immune deficiency (SCID) in order to study the effects of cytokines on the development of a malignant and fatal lymphoproliferative disease (LPD) of human B cell origin in this SCID-hu-PBL chimeric model. Based on the work of other investigators and our own preliminary data, we hypothesize that a dysregulation in human T cell cytokine production results in a dominant Type 2 (humoral) response, providing the requisite B cell stimulation in the SCID-hu-PBL mouse for progression to fatal LPD. A corollary to this would be that exogenous administration of factors responsible for the Type 1 (cellular) immune response could, as has been shown in vitro, promote a Type 1 immune response in vivo and thus prevent the critical B cell stimulation in vivo. Furthermore, we hypothesize that similar mechanisms may be operative as critical 'cofactors' in the genesis of EBV+ and EBV- AIDS lymphomas. In this proposal, we present preliminary data in support of this hypothesis. We show that depletion of human CD4+ cells decreases B cell stimulation, and chronic administration of a low, non toxic dose of recombinant IL-2, effectively prevents the development of LPD in the SCID-hu-PBL mouse, and we identify the cellular elements which are critical in this protective effect. We propose to fully test our hypothesis by characterizing the constitutive cytokine and cytokine receptor gene expression of human T cells in SCID-hu-PBL mice. We will compare this profile in SCID-hu-PBL mice at high risk for fatal LPD with SCID-hu-PBL mice at low risk for fatal LPD. We propose to prove cause and effect by counter regulating cytokine production and assessing for fatal LPD. We further postulate that a dominant Type 2 cytokine profile exists in vivo for individuals with AIDS lymphoma, and propose to characterize constitute-T cell cytokine and cytokine receptor gene expression in these patients to prove or disprove this postulate. Finally, we will continue our characterization of cytokines and cytokine receptor gene expression in both SCID-hu tumor and tumor specimens from patients with AIDS lymphoma, in an attempt to elucidate their contribution to malignant autocrine growth and the promotion of the Type 2 immune response.
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