T cell optimization for graft-versus-leukemia responses

Biernacki, Melinda A.; Sheth, Vipul; Bleakley, Marie

doi:10.1172/jci.insight.134939

Cited by 28 publications

(21 citation statements)

References 171 publications

(178 reference statements)

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“…If any or all of these functions are disrupted, then alloreactive T cells will be unable to induce GVHD. However, it is not ideal to fully disrupt all of these functions, because the same processes also mediate protection against infection post-transplant (35, 36). Here, we show that survival is reduced and exhaustion is increased in donor CD4 T cells from TCF-1-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

TCF-1 in CD4 T cells regulates GVHD severity and persistence

Harris

Mammadli

et al. 2021

Preprint

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Graft-versus-host disease (GVHD) is a leading cause of mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mature donor T cells in the graft mediate graft-versus-leukemia (GVL) responses against residual tumor cells, which may persist after pre-transplant conditioning regimens. Importantly, the same mature T cells also mediate GVHD. The transcription factor T Cell Factor-1 (TCF-1) is critical for T cell development in the thymus. Using a unique mouse model of allo-HSCT leading to GVHD, we investigated the role of TCF-1 in alloactivated T cell functioning and in GVHD. Here, we report that loss of TCF-1 in mature CD4 T cells reduces GVHD severity and persistence, improving survival of recipient mice. This was due to reduced proliferation, survival, and cytokine production of T cells, as well as increased exhaustion. Gene pathways involved in cytokine response, immune signaling, chemokine signaling, cell cycle, and T cell differentiation were altered by loss of TCF-1 in donor cells. Our companion paper shows that regulation of alloactivated CD4 T cells by TCF-1 differs from regulation of CD8 T cells, suggesting that TCF-1 plays a unique role in each subset. Therefore, targeting of TCF-1 or downstream signaling pathways may be an effective strategy for reducing GVHD following allo-HSCT.

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Section: Discussionmentioning

confidence: 99%

TCF-1 in CD4 T cells regulates GVHD severity and persistence

Harris

Mammadli

et al. 2021

Preprint

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“…The composition of allogeneic grafts is of vital importance for clinical outcomes 5 . The key components of allogeneic grafts include hematopoietic stem/progenitor cells, T cells, B cells, NK cells, dendritic cells (DCs), and so on 6 . The optimal composition of grafts has not been determined, but there has been great progress in identifying the effects of various cellular components among grafts during recent decades.…”

Section: To Optimize Graft Composition By Graft Engineeringmentioning

confidence: 99%

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

Huang

2021

Stem Cells Translational Medicine

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematological diseases. It is well known that allogeneic grafts play a key role in predicting transplantation prognosis. Hematopoietic stem cells (HSCs) are a functional part of grafts and are capable of reconstructing hematopoiesis and immunity, but purified HSCs have not been identified or isolated to date. In clinical practice, allogeneic grafts have been optimized to improve transplantation outcomes. The optimized grafts are considered to engraft successfully, reconstruct immunity rapidly, and exert a graft-vs-leukemia (GVL) effect without causing severe graft-vs-host disease (GvHD). In the last several decades, considerable efforts have been made in searching for optimized grafts based on different graft manipulation approaches and different graft sources. Currently, there is no uniform standard for optimized grafts in allogeneic transplantation. In the future, sorting out the cellular elements responsible for the effects of allo-HSCT might be a research direction for further optimization of grafts. In this review, we propose the concept of optimized grafts and summarize the recent advances made in the process of optimizing grafts.

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“…Such understanding might result in the generation of vaccines or of activated T cells that would selectively target hematopoietic antigens and enable exclusive destruction of tumor cells, rather than causing general GvHD. 135,136 Another promising approach has been reducing the pre-transplant tumor burden through targeted RIT. Most often RIT have included monoclonal antibodies to the hematopoietic cell surface antigen, CD45, or the B-cell antigen CD20, which are coupled to a radioactive isotope, and then added to a minimal-intensity conditioning regimen.…”

Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

History of hematopoietic cell transplantation: challenges and progress

Granot

Storb

2020

haematol

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After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.

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T cell optimization for graft-versus-leukemia responses

Cited by 28 publications

References 171 publications

TCF-1 in CD4 T cells regulates GVHD severity and persistence

TCF-1 in CD4 T cells regulates GVHD severity and persistence

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

History of hematopoietic cell transplantation: challenges and progress

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