Deficient cytokine response of human allergen-specific T lymphocytes from humanized SCID mice and reconstitution by professional antigen- presenting cells

Abstract

Background: Hu-PBL-SCID mice generated by the transfer of PBMCs from atopic individuals may provide a physiologic in vivo model for investigating human responses to allergens and potential approaches toward immunotherapy. Objective: This study was undertaken to investigate the functional activity and cytokine profile of human allergen-reactive T lymphocytes isolated from hu-PBL-SCID mice. Methods: PBMCs from allergic individuals were coinjected with allergen into SCID mice. Human lymphocyte migration and phenotype were established by reverse transcription-PCR and immunohistochemistry, IgE levels in sera were determined, and the frequency of allergen-reactive cytokine- producing T lymphocytes was established. Results: After immunization with allergen, specific IgE levels in hu-PBL-SCID sera were comparable with levels in donor sera. Although the majority of lymphocytes remained in the peritoneum, significant numbers of T lymphocytes were located in the spleen, where human IL-4, IL-5, and IFN-γ messenger RNA expression was detected after stimulation with PHA and phorbol myristate acetate. Failure to induce cytokine production by human T lymphocytes isolated from the peritoneum and spleen of hu-PBL-SCID mice by allergen was reversed by stimulating with allergen in the presence of exogenously added IL-2 and antigen-presenting cells (APC), particularly CD14+ monocytes. Under these conditions, allergen- reactive T cells expressed a T(H)2-like phenotype. Conclusions: These data suggest that, after initial activation and induction of antibody production, human T lymphocytes enter a state of unresponsiveness, arising from a loss of human professional APC, in hu-PBL-SCID mice. The use of hu-PBL-SCID mouse models in studies on therapeutic approaches for allergy may benefit from the additional transfer of human professional APC.