Of man in mice: Human-mouse chimeras as in vivo model systems for studying human hematopoiesis, immunology and HIV infection

Abstract

The overall goal of this thesis was the development of an animal model system that would permit the in vivo study of human hematopoiesis, immunology and infection with human specific pathogens such as HIV. To this end thymus (T), liver (L), and bone marrow (BM) were transplanted into SCID mice. Three models were pursued: (1) T/L-SCID-hu mice were constructed by implanting human fetal thymus and liver under the kidney capsules of SCID mice. The implant grew significantly and resembled normal human thymus. The mice were populated with high numbers of circulating human T-cells, whose phenotype and function resembled that of normal mature human fetal T-cells including their responsiveness to in vivo cytokine therapy with human recombinant IL-10 and IL-12. (2) BM-SCID-hu were generated by i.v. infusion of human fetal BM into irradiated SCID mice. Subsequent maturation of human B cells and monocytes in the mouse bone marrow occurred without administration of exogenous human growth factors. The endogenous expression of human IL-7, M-CSF and LIF mRNA by the transplanted BM cells was detected suggesting that these factors were sufficient to support the maturation of human stem/precursor cells in the mouse. (3) BM-T/L-SCID-hu, combining the above described models, produced high numbers of circulating mature human T- and B-cells. Finally, T/L-SCID-hu mice were successfully infected with primary patient isolates and laboratory adapted strains of HIV either by direct intraimplant injection of HIV or by peripheral inoculation. Infected mice displayed typical pathological signs of AIDS (thymic destruction, depletion of CD4 cells) only with some strains of HIV. The high number of circulating human T-cells in our T/L-SCID-human permitted us to investigate viral dissemination in vivo and these studies indicated that HIV infection leads to T-cell activation. The various models are being used to evaluate therapeutic interventions in HIV infection, and to observe the effects of experimental manipulations on the in vivo maturation and function of the human hematopoietic and immune systems.