Basophils inhibit proliferation of CD4+T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease

Abstract Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

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Expression of the T-Cell Activation Antigen, OX-40, Identifies Alloreactive T Cells in Acute Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v89.12.4652 ◽

1997 ◽

Vol 89 (12) ◽

pp. 4652-4658 ◽

Cited By ~ 66

Author(s):

Thomas V. Tittle ◽

Andrew D. Weinberg ◽

Cara N. Steinkeler ◽

Richard T. Maziarz

Keyword(s):

T Cells ◽

T Cell Activation ◽

Graft Versus Host Disease ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cell Activation ◽

Peripheral Blood Lymphocytes ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Abstract The OX-40 molecule is expressed on the surface of recently activated T lymphocytes. The presence of OX-40 on CD4+ T cells was analyzed in a rat haplo-identical (parental → F1) bone marrow transplant model of acute graft-versus-host disease (aGVHD). Increased numbers of activated CD4+ T cells that expressed the OX-40 antigen were detected in peripheral blood soon after transplantation before the earliest sign of disease. The peak of OX-40 expression occurred 12 days posttransplantation with a range of 18% to 36% of circulating T cells and remained 10-fold above background, never returning to baseline. A slight increase in OX-40 expression (range, 1% to 6%) was also detected on peripheral blood lymphocytes from control syngeneic F1 → F1 recipients. OX-40+ T cells were isolated from spleen, skin, lymph node, and liver tissue of rats undergoing aGVHD, but not in syngeneic transplants. OX-40+ T cells isolated from these tissues were of donor origin and were shown to be allo-reactive. These data raise the possibility of using the OX-40 antibody to detect and deplete selectively the T cells that cause aGVHD.

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Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease

Blood Advances ◽

10.1182/bloodadvances.2018027474 ◽

2019 ◽

Vol 3 (7) ◽

pp. 984-994 ◽

Cited By ~ 6

Author(s):

Jennifer S. Whangbo ◽

Haesook T. Kim ◽

Sarah Nikiforow ◽

John Koreth ◽

Ana C. Alho ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Low Dose ◽

B Cell Lymphoma ◽

Host Disease ◽

Graft Versus Host ◽

Response Groups

Abstract Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8+ T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor β (TCRβ) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.

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Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease

Blood ◽

10.1182/blood-2004-01-0328 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1565-1573 ◽

Cited By ~ 148

Author(s):

Britt E. Anderson ◽

Jennifer M. McNiff ◽

Catherine Matte ◽

Ionna Athanasiadis ◽

Warren D. Shlomchik ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Acute Gvhd ◽

Cell Receptor ◽

Host Disease ◽

Graft Versus Host ◽

Pathologic Features ◽

Radiation Resistant ◽

Tcr Diversity

Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly common cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Relative to acute GVHD (aGVHD), much less is understood about cGVHD. Using the B10.D2 → BALB/c murine cGVHD model, which shares critical pathologic features with human cGVHD, we find that radiation-resistant host T cells regulate cGVHD. We initially observed that recipients lacking all lymphocytes developed accelerated and more severe cGVHD. Using genetically deficient recipients, we determined that αβ+CD4+ T cells were required to regulate cGVHD. Increased cGVHD severity was not due to the absence of T cells per se. Rather, the potency of regulation was proportional to host T-cell receptor (TCR) diversity. Only CD4+CD25+, and not CD4+CD25-, host T cells ameliorated cGVHD when added back, indicating that host T cells acted not via host-versus-graft activity or by reducing homeostatic proliferation but by an undefined regulatory mechanism. Thus, preparative regimens that spare host CD4+CD25+ T cells may reduce cGVHD. Donor CD4+CD25+ T cells also reduced cGVHD. Depletion of CD4+CD25+ cells from the inoculum exacerbated disease, whereas transplantation of additional CD4+CD25+ cells protected against severe cGVHD. Additional CD4+CD25+ cells also promoted healing of established lesions, suggesting that their effects persist during the evolution of cGVHD.

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IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host Disease

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2013.11.007 ◽

2014 ◽

Vol 20 (2) ◽

pp. 192-201 ◽

Cited By ~ 9

Author(s):

Elizabeth O. Stenger ◽

Brian R. Rosborough ◽

Lisa R. Mathews ◽

Huihui Ma ◽

Markus Y. Mapara ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Host Disease ◽

Graft Versus Host ◽

Ifn Γ

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Interleukin-2 inhibits polarization to T helper type 1 cells and prevents mouse acute graft-versus-host disease through up-regulating suppressors of cytokine signalling-3 expression of naive CD4+ T cells

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2010.04089.x ◽

2010 ◽

Vol 160 (3) ◽

pp. 479-488 ◽

Cited By ~ 10

Author(s):

J. Zhao ◽

T. Zhang ◽

H. He ◽

Y. Xie

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Interleukin 2 ◽

T Helper ◽

Host Disease ◽

Graft Versus Host ◽

Helper Type ◽

Acute Graft

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Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4+ T-cells

Cellular and Molecular Life Sciences ◽

10.1007/s00018-013-1476-0 ◽

2013 ◽

Vol 71 (11) ◽

pp. 2135-2148 ◽

Cited By ~ 14

Author(s):

Stephan Fricke ◽

Nadja Hilger ◽

Christian Fricke ◽

Uta Schönfelder ◽

Gerhard Behre ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Ex Vivo ◽

Host Disease ◽

Graft Versus Host ◽

Graft Versus Leukemia ◽

Graft Versus Leukemia Effect

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Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease

Blood ◽

10.1182/blood-2006-08-043612 ◽

2007 ◽

Vol 110 (2) ◽

pp. 776-782 ◽

Cited By ~ 29

Author(s):

Juyang Kim ◽

Hye J. Kim ◽

Keunhee Park ◽

Jiyoung Kim ◽

Hye-Jeong Choi ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Costimulatory Molecule ◽

Tumor Necrosis Factor Receptor ◽

Host Disease ◽

Graft Versus Host ◽

Dominant Feature ◽

Current Therapies ◽

Necrosis Factor

Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2→Balb/c (H-2d) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T-cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4+ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.

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