PD-1/PD-L1 Interactions Contribute to Functional T-Cell Impairment in Patients Who Relapse with Cancer After Allogeneic Stem Cell Transplantation
Wieger J. NordeFrans MaasWillemijn HoboAlan J. KormanMichael QuigleyMichel G.D. KesterKonnie M. HebedaJ.H. Frederik FalkenburgNicolaas SchaapTheo M. de WitteRobbert van der VoortHarry Dolstra
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Abstract Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8+ T cells specific for the tumor. We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here, we offer functional and mechanistic support for this hypothesis, based on immune inhibition by programmed death-1 (PD-1) expressed on MiHA-specific CD8+ T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-γ production of MiHA-specific T cells cocultured with PD-L1–expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T-cell responses displayed high PD-L1 expression on CD34+ leukemia cells and increased PD-1 levels on MiHA-specific CD8+ T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8+ memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease. Cancer Res; 71(15); 5111–22. ©2011 AACR.P1180 Aims: In the initial days after transplantation hyperglycemia has been related to increasedβcell death and reducedβcell mass, suggesting that transitory hyperglycemia could have a positive effect on transplanted islets. The aim of this study is to identify the insulin treatment that can reduce βcell death after syngeneic islet transplantation. And to test whether insulin treatment to recipient before and after transplantation can save the number of transplanted islet. Methods: Male Lewis rats aged 8-10weeks were used as donors and recipients of transplantation. Islets were isolated by collagenase digestion and histopaque separation method and hand-picked under a dissecting microscope. Islets were cultured for 5days and transplanted into the renal subcapsular space of streptozotocin induced diabetic rats. Three groups of recipient were studied. Group1 (n=6): no insulin treatment; Group2 (n=6): insulin treatment from day 7 before transplantation to transplantation day; Group3(n=6): insulin treatment from day 7 before transplantation to day 7 after transplantation. In each group, 250 islets and 500 islets were transplanted. Blood glucose were measured 28 day after transplantation. Nephrectomy was performed on day 28 and graft was examined in histology (hematoxylin and eosin stain) and immunohistochemistory (insulin stain). Results: In each group, recipient rats transplanted 500 islets maintained normoglycemia throughout the initial 14days. Islet grafts were nice looking and well vascularized. Histologically, these grafts contained abundantβcell. On the other hand, in group3 recipient rats transplanted 250 islets maintained normoglycemia and grafts contained enoughβcell, but failed in that of group1 and group2. Conclusions: Insulin-induced normoglycemia in the initial 7days after islet transplantation could maintain the islets graft in good condition. As a result, we could reduce transplanted islets (250 islets) to maintain normoglycemia.
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OBJECTIVE To summarize the characteristics of adult stem cells and to introduce the definition and the features of stem cell disease. METHODS Literature concerning adult stem cells and stem cell disease was extensively reviewed. RESULTS Adult stem cells were localized in tissues and organs, and were able to generate function cells to replace cell loss during a lifetime of wear and tear. The stem cells had self-renewal to maintain themselves and undergo aging within the lifespan of an organism. The dysfunction of stem cells was capable to cause diseases, which could be defined as stem cell disease in human. The disorder of self renewal and differentiation in stem cells could increase the cellular proliferation, produce proliferative diseases such as tumors. The stem cells with self renewal defect, differentiation blockage, or aged stem cells could not supply enough function cells for tissue refreshment. The defect of tissue refreshment caused degenerative diseases. CONCLUSION Studies on the stem cell self renew, differentiation, and aging can provide knowledge to understand the mechanism of stem cell diseases and develop technique to diagnose and treat these diseases.
Stem Cell Therapy
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Objective To summary the characteristics of adult stem cells and to introduce the definition and the features of stem cell disease.Methods Literature concerning adult stem cells and stem cell disease was extensively reviewed.Results Adult stem cells were localized in tissues and organs,and were able to generate function cells to replace cell loss during a lifetime of wear and tear.The stem cells had self-renewal to maintain themselves and undergo aging within the lifespan of an organism.The dysfunction of stem cells was capable to cause diseases,which could be defined as stem cell disease in human.The disorder of self renewal and differentiation in stem cells could increase the cellular proliferation,produce proliferative diseases such as tumors.The stem cells with self renewal defect,differentiation blockage,or aged stem cells could not supply enough function cells for tissue refreshment.The defect of tissue refreshment caused degenerative diseases.Conclusion Studies on the stem cell self renew,differentiation,and aging can provide knowledge to understand the mechanism of stem cell diseases and develop technique to diagnose and treat these diseases.
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Stem Cell Therapy
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Numerous assays exist that measure the function of stem cells. In this article, we review in detail the history and future of existing stem cell assays. Hematopoietic stem cells (HSCs) are historically the most well studied, but new developments in stem cell research, including the claim of stem cell plasticity, have caused controversies related to technical issues, as well as to semantics. Stem cell research requires proper definitions, and utilization of stem cell assays, especially since research on non-HSCs that lack solid stem cell assays, is rapidly evolving. These emerging fields may benefit from what has been learned from HSC assays: most important, that the true potential of stem cells can only be assessed retrospectively. This also relates to new developments in HSC research, when limiting numbers of in vitro-manipulated stem cells are transplanted. The most conflicting results arise when cells express stem cell characteristics in one assay but not in another. Should we adjust our definition of a stem cell? If so, when do we decide a claim of stem cell activity to be justified? We therefore recommend using multiple stem cell assays, preferably at least one in vivo assay. These assays should measure functionality of the putative stem cell population.
Hematopoietic stem cell
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Hematopoietic stem cell
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This paper proposes that the previous division history of each stem cell is one determinant of the functional organization of the haemopoietic stem cell population. Stem cells from a lineage of stem cells which have generated many stem cells (older stem cells) are used in the animal to form blood before stem cells which have generated few stem cells (younger stem cells). The stem cell generating capacity of a lineage of stem cells is finite. After a given number of generations a stem cell is lost to the stem cell compartment by forming two committed precursors of the cell lines. Its part in blood formation is taken by the next oldest stem cell. We have called this proposal the generation-age hypothesis. Experimental evidence in support of the proposal is presented. We stripped away older stem cells from normal bone marrow and 13 day foetal liver with phase-specific drugs and revealed a younger population of stem cells whose capacity for stem cell generation was three- to four-fold greater than that of the average normal, untreated population. We aged normal stem cells by continuous irradiation and serial retransplantation and found that their stem cell generative capacity had declined eight-fold. We measured the stem cell generative capacity of stem cells in the bloodstream. It was a half to a quarter that of normal bone marrow stem cells and we found a subpopulation of circulating stem cells whose capacity for stem cell generation was an eighth to a fortieth that of normal femoral stem cells. This subpopulation was identified by its failure to express the brain-associated antigen which was present on 75% of normal femoral stem cells but was not found on their progeny, the committed precursors of granulocytes.
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Small cell size preserves the function of hematopoietic stem cells (HSCs); HSC enlargement during aging causes their dysfunction.
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Stem cells hold the promise of novel therapy for treating diseases. Unfortunately, the use and study of embryonic stem cells are currently clouded by ethical controversy. Adult stem cells offer a unique alternative in that they may be isolated, studied, or manipulated without harming the donor. Currently, several obstacles for use of adult stem cells as therapy exist. First, the ability to identify most adult stem cells is impeded by lack of stem cell markers. Second, in vitro systems for manipulating adult stem cell populations are often not well defined. Finally, our understanding of how adult stem cells are regulated within their niche is in its infancy. Next to the hematopoietic stem cell, epithelial stem cells are one of the most widely studied stem cell populations. Even so, the diversity between epithelial functions in different organs makes it difficult to determine whether common themes exist in regulating these related stem cells. Although each epithelial stem cell niche possesses unique features to facilitate its specialized functionality, they likely share many common aspects of regulation. The purpose of this review is to compare how the cell signaling influences the stem cell and its niche in rapidly self-renewing epithelia.
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