Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs

Beilhack, Andreas; Schulz, Stephan; Baker, Jeanette; Beilhack, Georg F.; Nishimura, Ryosei; Baker, Enosh M.; Landan, Gilad; Herman, Edward I.; Butcher, Eugene C.; Contag, Christopher H.; Negrin, Robert S.

doi:10.1182/blood-2007-09-112789

Cited by 106 publications

(122 citation statements)

References 50 publications

(90 reference statements)

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“…16,17 In contrast, other studies suggested that knockout of b7 was insufficient to modify intestinal GVHD, 18 and that blocking entry to specific secondary lymphoid organs (either peripheral lymph nodes or Peyer's patches) had no effect on GVHD, suggesting redundancy in secondary lymphoid tissue compartments. 19,20 Drawing general conclusions from these individual studies is difficult because of differences in the immunology of GVHD specific to the individual mouse models of HCT used in each of these separate studies. The evidence does support the theory that acute GVHD is initiated by allogeneic activation in secondary lymphoid tissue, with the induction of a specific trafficking phenotype dependent on the location of the secondary lymphoid tissue.…”

Section: Discussionmentioning

confidence: 99%

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

McDonough

Chen

et al. 2012

Bone Marrow Transplant

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Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). a4b7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n ¼ 15), skin GVHD (n ¼ 20) and no GVHD (n ¼ 10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of a4b7 integrin-expressing memory CD8 þ T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P ¼ 0.03. No differences were found in a4b7 expression in any CD4 þ T-cell subsets or naive CD8 þ T cells. This study adds to the evidence that a4b7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD.

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Section: Discussionmentioning

confidence: 99%

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

McDonough

Chen

et al. 2012

Bone Marrow Transplant

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“…6,13 Lack of CCR7 and CD62L expression on CTLs prevents migration to secondary lymphoid organs and further antigenic restimulations, although GVHD induction is only prevented if T-cell entry to all secondary lymphoid organs is impaired. 27 Expression of a 4 b 7 integrins, PSGL-1 and CXCR3 of CTLs, however, might facilitate entry into GVHD target organs but also into inflamed tissues, such as tumors. 28 Homing of CTLs into tumor sites was supported by the finding that the mastocytoma cell line P815 could be totally eradicated by CTLs, whereas the more aggressive B-ALL cells were only eradicated when injected with very low cell numbers.…”

Section: Discussionmentioning

confidence: 99%

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

et al. 2011

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Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8 þ cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigenpresenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4 þ or CD8 þ T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-c and TNF-a or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8 þ T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.

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“…60 (5) Geographic location: the interaction between the APCs and the donor T cells occurs primarily in the secondary lymph nodes, although in vivo imaging suggests that it also occurs in Peyer's patches. 61 However, although the secondary lymphoid organs are the likely location for the interaction of APCs and T cells, they are not obligatory for the development of GVHD. 62 Mediators of GVHD Donor T cells are the critical mediators of acute GVHD regardless of the type of antigen severity (Figure 2).…”

Section: Sensors Of Gvhdmentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

Sun

et al. 2009

Bone Marrow Transplant

157

126

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The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

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Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs

Cited by 106 publications

References 50 publications

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

New perspectives on the biology of acute GVHD

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