Treatment of systemic and organ-specific autoimmune disease in mice by allogeneic bone marrow transplantation

Abstract

Autoimmune diseases have been clinically divided into those which are systemic and organ-specific. (NZB X NZW) F1, MRL/1, and BXSB mice have been utilized as models for systemic autoimmune diseases. When these mice which had already developed autoimmune diseases were irradiated and reconstituted with T cell-depleted allogeneic bone marrow cells, the recipient survived for more than 5 months without showing graft-versus-host reaction. Immunohistopathological studies revealed that deposits of immunoglobulin and complement into the glomeruli were markedly reduced. In addition, levels of circulating immune complexes and auto-antibodies such as anti-dsDNA and anti-Sm antibodies decreased. Three months after bone marrow transplantation, T cell dysfunction was restored, and hyperfunction of B cells and macrophages were normalized. These data prompted us to examine whether or not organ-specific autoimmune diseases can be treated by allogeneic bone marrow transplantation. NOD mice which develop insulitis and overt diabetes were used for this experiment. The mice showed marked infiltration of T cells into the pancreatic islets which resulted in selectively destroying beta cells. Most of the T cells are Lyt-1+, and some are Lyt-2,3+. When NOD mice (6 months old) were irradiated and reconstituted with bone marrow cells of young BALB/c nu/nu mice (less than 2 months), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in the mesangial area of the glomeruli disappeared 3 months after bone marrow transplantation. Assays for immunological functions revealed that NOD mice showed hyperfunction of T cells, B cells, and macrophages. In NOD mice reconstituted with BALB/c nu/nu bone marrow cells, these functions were normalized. Newly developed T cells are found to be tolerant of both bone marrow donor-type and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation is a strategy to be considered as an approach to the treatment for both systemic and organ-specific autoimmune diseases in humans.