The chimeric SCID mouse in studies of the human immune system

Several methods have been developed to transfer components of the human immune system into mice. In particular, the adoptive transfer of human Iymphoid cells or tissues into mice with severe combined immunodeficiency (SCID mice) has demonstrated the general applicability of such an approach. SCID mice have an autosomal recessive defect that impairs the rearrangement of antigen receptor genes in Iymphoid progenitors. Lack of an effective immune response, coupled with the intact hematopoietic microenvironment, allows the SCID mice to be reconstituted with human cells. Intraperitoneal transfer of human peripheral blood Iymphocytes was utilized to reconstitute the animals. Homing of human cells into mouse tissues and the synthesis of human immunoglobulins in chimenc SCID mice were analyzed. The effect of pretreatment regimens such as total body irradiation as well as the inf1uence of the source of cells on human immunoglobulin synthesis were investigated.

Studies were performed to characterize animals repopulated with cells from individuals with primary immunoglobulin deficiencies and autoimmunity. The effect of gammaglobulin treatment on autoantibody production was investigated in SCID mice engrafted with cells from patients with primary biliary cirrhosis. Human antimitochondrial antibodies could be detected in reconstituted animals. Treatment with human gammaglobulin resulted in a rapid decrease of autoantibodies in the circulation. SCID mice engrafted with Iymphocytes from donors seropositive for Epstein-Barr virus frequently develop Iymphoproliferative disease of human origin. The antitumor effect of various treatment modalities such as antiviral or gammaglobulin treatments was studied in the chimeric SCID mice. A preventive effect of gammaglobulin treatment on tumor formation was found which was shown to be due to the presence of antibodies directed to Epstein-Barr virus-related antigens in the gammaglobulin preparations. The last study was aimed at developing a mouse model of suicide gene therapy for human plasma cell tumors. SCID mice were injected subcutaneously with human myeloma cell lines transduced with a herpes simplex thymidine kinase gene and subsequently treated with ganciclovir. An in vivo bystander effect was noticed when mice received mixtures of transduced and unmodified cells.