Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Type 1 diabetes (T1D) is an autoimmune disorder characterized by destruction of the pancreatic beta cells by both humoral- and cell-mediated immune mechanisms. Transplantation of hematopoietic stem/progenitor cells (HSPC) has been suggested as a novel therapy for T1D. Here, we evaluated if bone marrow cells (BMC) from allogeneic CD4 knockout (KO), CD8 KO or μMT (B cell deficient) mice prevent diabetes in non-obese diabetic (NOD) mice.
*Methods: We first tested if HSPC from congeneic non-obese diabetic resistant (NOR) mice prevent diabetes in NOD mice. 1,000 sorted Sac-1+/c-Kit+/Lin– HSPC of congeneic donor NOR mice or syngeneic donor NOD mice were transplanted into five- to six-week-old pre-diabetic NOD mice conditioned with 950 cGy total body irradiation (TBI). Eighty-three percent of NOD recipients (n = 6) of NOD HSPC developed hyperglycemia by 9 months. 100% (n = 7) of NOD control mice that received TBI only or 70% (n = 20) of unmanipulated NOD mice developed diabetes at 6 months or 7 months, respectively. Significant insulitis was observed in diabetic mice by H&E staining and immunohistochemical analysis of pancreatic inflammation demonstrated that islet infiltrates are composed primarily of CD4+ lymphocytes. In contrast, all NOD recipients (n = 9) of congeneic donor NOR HSPC remained normoglycemic with a follow-up time of more than 9 months. Next, we tested if BMC from allogeneic B6 mice prevent diabetes in NOD mice. Pre-diabetic NOD recipients were treated intraperitoneally with anti-CD8 mAb (1 ml/mouse) on day -2. 30 x 106 BMC from donor wild-type B6 mice were transplanted into NOD recipients conditioned with 750 cGy of TBI 4-6 hrs after conditioning on day 0. Recipients were treated intraperitoneally with anti-CD154 mAb (0.5 mg/mouse) on day 0 and +2. All NOD (n = 4) recipients engrafted, with 93% ± 4% donor cell chimerism. All NOD recipients remained normoglycemic with a follow-up time of more than 17 months. To test if BMC from allogeneic CD4 KO, CD8 KO, μMT (B cell deficient) B6 mice prevent diabetes, 30 x 106 BMC from donor CD4 KO, CD8KO, or µMT B6 mice were transplanted into similarly conditioned pre-diabetic NOD recipients.
*Results: All NOD recipients of BMC from CD4 KO, CD8 KO or μMT mice engrafted. The levels of donor chimerism in recipients of BMC from CD4 KO, CD8 KO or μMT mice were 97% ± 2%, 93% ± 2% and 92% ± 8%, respectively. All NOD recipients exhibited normal blood glucose levels with long-term survival of more than 17 months.
*Conclusions: We conclude that diabetes-development was blocked in all NOD mice that engrafted with allogeneic BMC. These data demonstrate that allogeneic BMC transplantation prevents the development of diabetes, even if the HSPC is from donors lacking T cells (CD4 or CD8) or B cells.
To cite this abstract in AMA style:Huang Y, Xu H, Wen Y, Ildstad S. Prevention of Diabetes in the NOD Mice Reconstituted with Bone Marrow Cells from Allogeneic CD4 Knockout, CD8 Knockout or B-Cell Knockout B6 Mice [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/prevention-of-diabetes-in-the-nod-mice-reconstituted-with-bone-marrow-cells-from-allogeneic-cd4-knockout-cd8-knockout-or-b-cell-knockout-b6-mice/. Accessed August 11, 2020.
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