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Understanding the Mechanisms of Graf...

Shaikh, Ahmad.

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Understanding the Mechanisms of Graft Rejection and Tolerance Induction after Nonmyeloablative Haploidentical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Understanding the Mechanisms of Graft Rejection and Tolerance Induction after Nonmyeloablative Haploidentical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease./
作者:	Shaikh, Ahmad.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	141 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27958616
ISBN:	9798645478209

Understanding the Mechanisms of Graft Rejection and Tolerance Induction after Nonmyeloablative Haploidentical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease.
Shaikh, Ahmad.

Understanding the Mechanisms of Graft Rejection and Tolerance Induction after Nonmyeloablative Haploidentical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 141 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--The Catholic University of America, 2020.

This item must not be sold to any third party vendors.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to significant morbidity and early mortality. Hematopoietic stem cell transplantation (HSCT) remains the most widely available curative approach for SCD. However, <18 % of SCD patients have human leukocyte antigen (HLA)-matched sibling donors. HLA-haploidentical (haplo) HSCT expands the donor pool considerably and it is a practical alternative for these patients, but with an increased risk of allograft rejection. Identifying unique diagnostic biomarkers and also elucidating the mechanisms of engraftment and rejection in SCD patients who underwent haplo-HSCT could potentially be helpful not only in predicting HSCT outcome, but also treating the impending graft rejection at a reversible state. We performed a proteomic analysis using plasma samples from engrafted and rejected SCD patients who underwent haplo-HSCT and found that galectin-1 (Gal-1), thrombospondin-1(Tsp-1), and platelet factor 4 (Pf-4) levels were significantly higher in engrafted patients. Next, in order to verify whether these findings can be replicated in a rodent bone marrow transplantation setting and to understand the cellular mechanism, we employed our major histocompatibility complex (MHC)-mismatched allogeneic (allo)-HSCT murine model. Transplanted mice were classified into either rejected or engrafted groups based on the presence of donor chimerism. In rejected mice, we noted significantly higher frequencies of conventional CD4+ T cells, subset of CD4+ T helper (Th) 17 cells, CD8+ T cells, NK cells; and pro-inflammatory cytokines TNF-a producing CD4+ T cells dendritic cells (DCs), macrophages, B cells, and CD8+ T cells, and IFN-g producing DCs and macrophages. Importantly cardinal features observed in engrafted mice include increased frequencies of Tregs, Tr1 cells, Th2 cells, and anti-inflammatory cytokine IL-10 positive CD4+ T cells, DCs and macrophages, and increased circulatory levels of Gal-1. Further, we delineated the association of circulatory levels of Gal-1 with enhanced proportions of Gal-1 producing CD4+ T cells, Th2 subset, Tregs, and Tr1 cells in engrafted mice. Elevated frequencies of Gal-1 positive Tregs contributed to increased Treg suppression activity, and the addition of Gal-1 siRNA resulted in attenuation of Treg suppression in engrafted mice. Additionally, our data indicated that Gal-1 positive CD4+CD25- effector T cells in engrafted mice are more susceptible to apoptosis. Here, we have shown for the first time that not only Gal-1 favors engraftment in SCD patients who underwent haplo-HSCT, but also Gal-1 contributes to bone marrow cell engraftment in our MHC-mismatched murine allo-HSCT model. Taken together, our results demonstrate that Gal-1 expressing Tregs, Tr1 and Th2 cells may play an essential role in inducing immune tolerance and stable mixed chimerism after HSCT.

ISBN: 9798645478209Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Hematopoietic stem cell transplant

Understanding the Mechanisms of Graft Rejection and Tolerance Induction after Nonmyeloablative Haploidentical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease.
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