Role of the PD-L1 Pathway in Regulating Alloreactive CD8+ T cell Metabolism, Survival and GVHD Capacity
Başlık:
Role of the PD-L1 Pathway in Regulating Alloreactive CD8+ T cell Metabolism, Survival and GVHD Capacity
Yazar:
Cassady, Kaniel Marvin, author.
ISBN:
9780438084766
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (140 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Defu Zeng; Arthur D. Riggs Committee members: David K. Ann; Peter P. Lee; Paul J. Martin; John C. Williams.
Özet:
Alloreactive donor T cell-mediated graft versus leukemia (GVL) activity during allogeneic hematopoietic cell transplantation (HCT) is a curative immunotherapy for hematological malignancies. However, the same alloreactive T cells also mediate a severe side effect: graft versus host disease (GVHD), which remains a major obstacle to the application of allogeneic HCT as a curative therapy for leukemia/lymphoma and autoimmune patients. While immunosuppressants can treat GVHD, severe side-effects of chronic immunosuppression, such as infection and tumor relapse, underscore the importance of developing novel regimens for the prevention and treatment of GVHD. Recent studies have implied a therapeutic possibility for targeting alloreactive T cell metabolism and/or immune checkpoint pathways, such as the PD-L1 pathway, for the prevention of GVHD; however, further mechanistic insight is required for the advancement of these studies for clinical application.
In my dissertation, using the murine GVHD model of C57BL/6 donor to BALB/c host, I dissected the specific metabolic pathways that alloreactive CD8 + T cells engage following HCT, as well as the impact of the PD-L1 pathway on both alloreactive CD8+ T cell metabolism, expansion and GVHD-capacity following HCT. I have observed the following after HCT: 1) alloreactive CD8+ T cells transition to a momentary state of increased glycolysis during activation, followed by an increase in mitochondrial expansion and fusion and reversion to mitochondrial respiration; 2) blockade of PD-L1/PD-1 interaction increases glycolytic capacity and ameliorates the transition to mitochondrial respiration to augment alloreactive CD8 + T cell-mediated GVHD; 3) increased glycolysis and GVHD pathogenesis observed in the absence of PD-L1/PD-1 interaction is dependent on PD-L1/CD80 interaction; 4) in the presence of PD-L1/PD-1 interaction, PD-L1/CD80 interaction plays a costimulatory role early during activation to augment CD8+ T cell expansion, while at the peak of T cell activation, PD-L1/CD80 is required for T cell metabolic reprogramming and tolerance to prevent GVHD; and, 5) PD-L1/CD80 interaction inhibits alloreactive CD8+ T cell mitophagy during the T cell contraction to ameliorate GVHD. These observations provide new insights into the pathogenesis of alloreactive CD8+ T cells during GVHD and lay a new scientific foundation for developing novel regimens to prevent GVHD.
Notlar:
School code: 0517
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(695095.1) | 695095-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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