Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells

Abstract

Patients with severe systemic lupus erythematosus (SLE) refractory to conventional treatment are candidates for autologous hematopoietic stem cell (HSC) transplantation if the intent is to reset the immunologic clock. These patients might be candidates for allotransplantation with (SLE)-resistant major histocompatibility complex (MHC) haplotype-matched HSC if partial or complete replacement of an autoimmune-prone system is the intent. Using lupus-prone New Zealand black ؋ New Zealand white (NZBW) mice, we investigated the use of highly enriched, haplomismatched, allogeneic HSC to prevent development of or to treat established autoimmune pathology. Young NZBW mice receiving purified allogeneic HSC transplants had improved survival, decreased proteinuria, circulating immune complexes, and autoantibodies to nuclear antigens than did untreated mice or mice given NZBW HSCs. NZBW mice with established lupus-like disease that received nonmyeloablative conditioning and transplants of (MHC) haplomismatched allogeneic HSCs also had greatly increased overall survival. Mice that received transplants exhibited stabilization or reversal of their lupus symptoms; stabilized or decreased proteinuria, and a lower frequency of elevated circulating immune complexes or autoantibodies than did control mice. Induction of durable mixed chimerism by transplantation of purified allogeneic HSCs after nonmyeloablative conditioning has the potential to reverse symptoms of established NZBW lupus. (Blood.

Allogeneic hematopoietic SCT for patients with autoimmune diseases

“…Animal models at least suggest that remission of experimental AD can be achieved after nonmyeloablative conditioning with mixed chimerism. 14 Overall, the heterogeneity of the patient population and of the data did preclude the identification of factors associated with response or mortality. This does not necessarily imply that all factors were equally important.…”

How One Thing Led to Another

“…And Judy Shizuru and I showed that C57BL-to-BALB/c chimeras had better minor histocompatibility T cell restriction to donor H2 b MHC than to thymic host (H2 d ) MHC, apparently contradicting the rules for MHC restriction established previously (15). Finally, we have shown that tolerance induction by HSCs from donors genetically resistant to diabetes and lupus can end the autoimmune components of these diseases in mice (18)(19)(20).…”

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

“…Sorted allogeneic stem cells recently have been shown to establish mixed chimerism in sublethally irradiated NZB/W F1 recipients and reverse overt lupus (21). However, 50% of the chimeric recipients continued to have high levels of serum autoantibodies, and Ϸ30% of the chimeric recipients continued to have proteinuria and eventually died of lupus (21).…”

“…Sorted allogeneic stem cells recently have been shown to establish mixed chimerism in sublethally irradiated NZB/W F1 recipients and reverse overt lupus (21). However, 50% of the chimeric recipients continued to have high levels of serum autoantibodies, and Ϸ30% of the chimeric recipients continued to have proteinuria and eventually died of lupus (21). This observation indicates that the pathogenic memory T and B cells continue to exist in the lupus recipients with mixed chimerism and continue to mediate lupus, and induction of complete chimerism may be required for the cure of lupus.…”