A multiple transgenic mouse model with a partially humanized activation pathway for helper T cell responses

Mice expressing human CD4 and human MHC II molecules provide a valuable mod el both for the investigation of the immunopathogenetic role of human autoa ntigens and for the development of therapeutic strategies based on modulati ng helper T cell activation in vivo. Here we present a novel mouse model ex pressing HLA-DR17 (a split antigen of HLA-DR3) together with human CD4 in t he absence of murine cd4 (CD4/DR3 mice). Human CD4 accurately replaces muri ne cd4 within T cells. In particular, the preservation of cds' and CD4(+) T cell subsets distinguishes CD4/DR3 mice from other multiple transgenic mod els in which the alternative T cell subsets are fundamentally disturbed. Mo reover, human CD4 is also faithfully expressed on antigen presenting cells such as dendritic cells and monocyte/macrophages, so that the overall trans genic CD4 expression pattern resembles Very closely that of humans. HLA-DRS expression in the thymus correlates very closely to that of mouse MHC II. In contrast, only 70% of mouse MHC II positive cells in spleen, lymph node, and peripheral blood coexpress HLA-DRS. No significant bias was found with regard to particular leucocytes in this respect. The stimulation of helper T cells clearly depends on the interaction between the human transgene pro ducts, since mAbs to HLA-DR and/or CD4 completely blocked in vitro recall r esponses to tetanus toroid. CD4/DR3 mice represent a partially humanized an imal model which will facilitate studies of DR3-associated autoimmune respo nses and the in vivo determination of the therapeutic potential of mAbs to human CD4. (C) 2000 Elsevier Science B.V. All rights reserved.