Elimination of insulitis and augmentation of islet β cell regeneration via induction of chimerism in overtly diabetic NOD mice

Abstract

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from autoreactive T cell destruction of insulin-producing ␤ cells. Cure of type 1 diabetes may require both reversal of autoimmunity and regeneration of ␤ cells. Induction of chimerism via allogeneic hematopoietic cell transplantation has been shown to reestablish tolerance in both prediabetic and diabetic NOD mice. However, it is unclear whether this therapy augments ␤ cell regeneration. Furthermore, this procedure usually requires total body irradiation conditioning of recipients. The toxicity of total body irradiation conditioning and potential for graft-versus-host disease (GVHD) limit the application of allogeneic hematopoietic cell transplantation for treating type 1 diabetes. Here we report that injection of donor bone marrow and CD4 ؉ T cell-depleted spleen cells induced chimerism without causing GVHD in overtly diabetic NOD mice conditioned with anti-CD3/CD8 and that induction of chimerism in new-onset diabetic NOD mice led to elimination of insulitis, regeneration of host ␤ cells, and reversal of hyperglycemia. Therefore, this radiation-free GVHD preventive approach for induction of chimerism may represent a viable means for reversing type 1 diabetes.hematopoietic cell transplantation ͉ type 1 diabetes ͉ anti-CD3-conditioning ͉ reversal of diabetes ͉ reversal of autoimmunity

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

“…We observed that conditioning with anti-CD3 alone was not sufficient for induc- tion of chimerism in old (Ͼ12-week-old) recipients, although it was sufficient in young (Ͻ8-week-old) recipients (11). Next, we tested whether the coinjection of low-dose SAHA could augment induction of chimerism in old recipients.…”

“…We recently reported that infusion of donor CD8 ϩ T or CD4 ϩ T-depleted spleen cells and BM cells induced chimerism without GVHD in nonautoimmune and autoimmune NOD mice (9)(10)(11). The mechanisms of GVHD prevention in the anti-CD3-conditioned recipients include confining donor CD8 ϩ T cells to host lymphohematological tissues and tolerizing the alloreactive T cells (10).…”

“…The mechanisms of GVHD prevention in the anti-CD3-conditioned recipients include confining donor CD8 ϩ T cells to host lymphohematological tissues and tolerizing the alloreactive T cells (10). The anti-CD3-conditioning regimen allows donor CD8 ϩ T cells to mediate graft versus host leukemia (GVL) activity and graft versus autoimmune (GVA) activity without causing GVHD (9)(10)(11). In addition, the chimeric NOD recipients with chimerism established by anti-CD3 conditioning showed regeneration of islet ␤-cells and reversal of diabetes (11).…”

“…The anti-CD3-conditioning regimen allows donor CD8 ϩ T cells to mediate graft versus host leukemia (GVL) activity and graft versus autoimmune (GVA) activity without causing GVHD (9)(10)(11). In addition, the chimeric NOD recipients with chimerism established by anti-CD3 conditioning showed regeneration of islet ␤-cells and reversal of diabetes (11). Therefore, the anti-CD3-conditioning regimen has the potential to promote allogeneic HCT for treating autoimmune diseases.…”

2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

“…[15][16][17][18] Ionizing irradiation has often been used in bone marrow transplants or to treat cancers with or without chemotherapy in clinics and experimental animal models. [19][20][21][22] Whole-body irradiation (WBI) significantly decreases the lymphocyte pool, and the various lymphocyte subsets have different sensitivities to irradiation. 23 It has been reported that ionizing radiation changes the Th1/Th2 balance.…”