Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT

被引:0
|
作者
Sidlik Muskatel, Rakefet [1 ,2 ]
Nathansohn-Levi, Bar [2 ]
Reich-Zeliger, Shlomit [2 ]
Mark, Michal [2 ]
Stoler-Barak, Liat [2 ]
Rosen, Chava [1 ]
Milman-Krentsis, Irit [1 ]
Bachar Lustig, Esther [1 ]
Pete Gale, Robert [3 ]
Friedman, Nir [2 ]
Reisner, Yair [1 ,4 ,5 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX USA
[2] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel
[3] Imperial Coll London, Haematol Res Ctr, Dept Immunol & Inflammat, London, England
[4] Canc Res, Austin, TX USA
[5] 435 Fannin St, Houston, TX 77054 USA
关键词
diabetes diseases; autoimmune diseases; hematopoietic stem cell transplantation; immunotherapy; BONE-MARROW-TRANSPLANTATION; CHIMERISM; TOLERANCE; HYPOGLYCEMIA; ALLOGRAFTS; INDUCTION; DELETION; ADULTS;
D O I
10.1093/stcltm/szad021
中图分类号
Q813 [细胞工程];
学科分类号
摘要
The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated the ability of this relatively safe transplant modality to eliminate autoimmune T-cell clones in the NOD mouse model which spontaneously develop T1DM. Our results demonstrate that using this approach, marked durable chimerism is attained, without any transplant-related mortality, and with a very high rate of diabetes prevention. TCR sequencing of transplanted mice showed profound changes in the T-cell repertoire and decrease in the prevalence of specific autoimmune T-cell clones directed against pancreatic antigens. This approach could be considered as strategy to treat people destined to develop T1DM but with residual beta cell function, or as a platform for prevention of beta cell destruction after transplantation of allogenic beta cells.
引用
收藏
页码:281 / 292
页数:12
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