LYMPHOPROLIFERATIVE DISEASE IN HUMAN PERIPHERAL-BLOOD MONONUCLEAR CELL-INJECTED SCID MICE - IV - DIFFERENTIAL ACTIVATION OF HUMAN TH1 AND TH2 LYMPHOCYTES AND INFLUENCE OF THE ATOPIC STATUS ON LYMPHOMA DEVELOPMENT

Intraperitoneal transfer of PBMC from EBV+ donors into SCID mice lends to high human Ig levels in mouse serum and B cell lymphoproliferative disease, As these events depend on the activation of coinjected human T cells, we addressed the behavior of the Th1 and Th2 subsets in this model, Production of IFN-gamma, but not of Th2 cytokines such as IL-4 , was detected in culture supernatants of PBMC stimulated in vitro wit h mouse splenocytes. Moreover, anti-CD3 stimulation of the human cells recovered from mice brought about IFN-gamma, but not IL-4, synthesis; on the other hand, PCR and in situ hybridization analysis of ex vivo- recovered cells disclosed the presence of mRNA for both cytokines foll owing in vitro restimulation, thus suggesting posttranscriptional regu lation of IL-4 gene expression, When SCID mice were inoculated with PB MC from atopic donors, whose Th1/Th2 profile displays an imbalance tow ard Th2 cells, tumor development rates were lower, and tumor latency w as higher, compared with those in mice injected with PBMC from normal donors, Isotypic analysis of human Ig in mouse serum showed the exclus ive presence of IFN-gamma-driven IgG subclasses; in addition, human Ig E were low or undetectable in most cases, These findings indicate that following transfer into SCID mice, human Th1 lymphocytes undergo pref erential activation, whereas Th2 function is down-regulated, Th1 lymph ocytes probably are a major component in promoting EBV+ B cell expansi on and tumor development; the individual Th1/Th2 profile could in part account for the as yet unexplained donor variability in tumor generat ion in this experimental model.