Effective graft depletion of MiHAg T-cell specificities and consequences for graft-versus-host disease

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3830-3838 ◽  
Author(s):  
Moniek A. de Witte ◽  
Mireille Toebes ◽  
Ji-Ying Song ◽  
Monika C. Wolkers ◽  
Ton N. M. Schumacher
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Graft Engineering

Abstract Minor histocompatibility antigen (MiHAg) differences between donor and recipient in MHC-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) often result in graft-versus-host disease (GVHD). While MiHAg-specific T-cell responses can in theory be directed against a large number of polymorphic differences between donor and recipient, in practice, T-cell responses against only a small set of MiHAgs appear to dominate the immune response, and it has been suggested that immunodominance may predict an important contribution to the development of GVHD. Here, we addressed the feasibility of graft engineering by ex vivo removal of T cells with 1 or more defined antigen specificities in a well-characterized experimental HSCT model (B6 → BALB.B). We demonstrate that immunodominant H60- and H4-specific CD8+ T-cell responses can be effectively suppressed through MHC class I tetramer–mediated purging of the naive CD8+ T cell repertoire. Importantly, the development of GVHD occurs unimpeded upon suppression of the immunodominant MiHAg-specific T-cell response. These data indicate that antigen-specific graft engineering is feasible, but that parameters other than immunodominance may be required to select T-cell specificities that are targeted for removal.

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Blood ◽  
2014 ◽  
Vol 123 (2) ◽  
pp. 290-299 ◽  
Author(s):  
Marie-Charlotte Brüggen ◽  
Irene Klein ◽  
Hildegard Greinix ◽  
Wolfgang Bauer ◽  
Zoya Kuzmina ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Responses ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Key Points ◽  
Cell Patterns

Key Points Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD. Increased TSLP expression is an indicator of acute cutaneous GVHD development.

scholarly journals MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice

Blood ◽  
2015 ◽  
Vol 126 (11) ◽  
pp. 1314-1323 ◽  
Author(s):  
Yongxia Wu ◽  
Jessica Heinrichs ◽  
David Bastian ◽  
Jianing Fu ◽  
Hung Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Responses ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Key Points ◽  
Leukemia Relapse

Key Points miR-17-92 is required for T cells to mediate GVHD but not the GVL effect. Targeting miR-17-92 with antagomirs efficiently alleviates GVHD.

scholarly journals CCR2 is required for CD8-induced graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3322-3330 ◽  
Author(s):  
Theis H. Terwey ◽  
Theo D. Kim ◽  
Adam A. Kochman ◽  
Vanessa M. Hubbard ◽  
Sydney Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Migration

AbstractGraft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.

scholarly journals Blockade of osteopontin reduces alloreactive CD8+ T cell–mediated graft-versus-host disease

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1723-1733 ◽  
Author(s):  
Fang Zhao ◽  
Yi Zhang ◽  
Hao Wang ◽  
Min Jin ◽  
Shan He ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.

CCR1 Expression on Donor Leukocytes Is Critical to the Development of Graft Versus Host Disease after Allogeneic SCT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3067-3067
Author(s):  
Gerhard C. Hildebrandt ◽  
Sung Choi ◽  
Krystyna M. Olkiewicz ◽  
Stephen W. Chensue ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Responses ◽  
Target Organ ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Donor Cells ◽  
The Impact

Abstract Acute graft versus host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-SCT) and limits the utility of this treatment strategy. The pathophysiology of aGVHD involves injury to host tissues by inflammatory cytokines and donor-derived cellular effectors, the recruitment of which is likely mediated by chemokine receptor: ligand interactions. CCR1 is expressed on various cell types such as T cells, monocytes and macrophages and binds to a group of CC chemokines that includes RANTES (CCL5) and Mip-1a (CCL3). In light of the previously described role for both donor T cells and monocytes in the development of aGVHD, we tested the hypothesis that CCR1 expression on donor leukocytes contributes to systemic and target organ inflammation that occurs in this setting by using a well established murine SCT model (B6→B6D2F1) and mutant mice deficient in CCR1. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed after SCT by survival and a clinical scoring system that incorporates changes in weight loss, fur texture, skin integrity, mobility and posture. As expected, syngeneic SCT recipients all survived and where indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD and only 50% of animals survived by day 35. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (1.0±0.3 vs. 3.0±0.5) compared to allo-CCR1+/+ controls. In addition, serum TNFa levels were significantly decreased by day +7 following CCR1−/− SCT (4.7±2.7 vs. 55.3±14.4 pg/ml) and correlated with a significant reduction in intestinal histopathology both on day 7 (16.3±1.0 vs. 21.5±0.9) and on day 14 (15.8±1.8 vs. 23.8±1.0). GVHD injury to liver and skin was mild at these time points and did not differ between allo groups. Next we investigated the impact of CCR1 expression on allo-specific T cell responses in vivo and found that by day +7 after SCT both splenic T cell expansion (3.7±0.4 vs. 9.6±0.9 x 106 cells) and serum IFNγ levels (4561±559 vs. 10028±681 pg/ml) were significantly lower when CCR1 was absent on donor cells. In summary, we describe a heretofore unknown role for CCR1 on donor leukocytes in the development of aGVHD. The improvement in systemic and target organ disease observed after CCR1−/− SCT may be attributed to 1) alterations in leukocyte recruitment to the intestinal tract resulting in improved intestinal integrity, reduced translocation of endotoxin and decreased TNFa production and 2) modulation of donor T cell responses to host allo-antigens. Experiments are ongoing to determine whether strategies targeting CCR1 signalling can be exploited to prevent GVHD but maintain GVL effects and thereby improve overall survival after allo-SCT.

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