Frequency of anti-recipient alloreactive helper T-cell precursors in donor blood and graft-versus-host disease after HLA-identical sibling bone-marrow transplantation

In two situations, transfer of normal unsensitized bone marrow cells into heavily irradiated H-2-identical allogeneic mice caused a high incidence of lethal chronic graft-versus-host disease (GVHD), i.e. mortality occuring between days of 20 and 80 postirradiation. Minor histocompatibility determinants appeared to be the main target for eliciting GVHD. Removing mature T cells from the marrow with anti-Thy 1.2 serum and complement before injection prevented GVHD. On the basis of adding purified T cells to T-cell-depleted marrow cells, it was concluded that contamination of the marrow with as few as 0.3% T cells was sufficient to cause a high incidence of lethal GVHD in certain situations. No GVHD was found with the injection of non-T cells (Thy 1.2-negative cells) or with tolerant T cells. Irradiated recipients of T-cell-depleted marrow cells remained in good health for prolonged periods. These mice showed extensive chimerism with respect to the donor marrow, normal numbers of T and B cells and were immunocompetent. The data provide no support for the view that chronic GVHD developing after bone marrow transplantation in man is the result of an attack by the progeny of the donor stem cells. The results imply that mature T cells contaminating marrow inocula are probably the main cause of GVHD seen in the clinical situation.

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Host-Specific Interleukin-2–Secreting Donor T-Cell Precursors as Predictors of Acute Graft-versus-Host Disease in Bone Marrow Transplantation between HLA-Identical Siblings

New England Journal of Medicine ◽

10.1056/nejm199212033272301 ◽

1992 ◽

Vol 327 (23) ◽

pp. 1613-1617 ◽

Cited By ~ 120

Author(s):

Matthias Theobald ◽

Thomas Nierle ◽

Donald Bunjes ◽

Renate Arnold ◽

Hermann Heimpel

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

T Cell ◽

Graft Versus Host Disease ◽

Marrow Transplantation ◽

Interleukin 2 ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

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Early CD30 Signaling Is Critical for Adoptively Transferred CD4+CD25+ Regulatory T Cells in Prevention of Acute Graft Versus Host Disease.

Blood ◽

10.1182/blood.v108.11.3176.3176 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3176-3176

Author(s):

Robert Zeiser ◽

Vu H. Nguyen ◽

Jing-Zhou Hou ◽

Andreas Beilhack ◽

Elizabeth A. Zambricki ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

T Cell ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Marrow Transplantation ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Abstract CD4+CD25+ regulatory T cells (Treg) have been demonstrated to reduce the severity of acute graft-versus-host disease (aGvHD) in murine models of bone marrow transplantation. However, the surface molecules that are critical for suppression are unclear. The TNF-R superfamily member CD30 has been shown to be expressed on regulatory T cells that down-modulate nickel specific immune responses and to be relevant for Treg mediated protection from allograft rejection. Deficiency of the CD30 molecule (CD30−/−) is associated with impaired thymic negative selection and augmented T cell autoreactivity. Therefore, we investigated the role of CD30 signaling in Treg function in an aGvHD model. Treg derived from CD30−/ − animals were significantly less effective in preventing aGvHD lethality (wt vs. CD30−/ − p=0.002). Signal intensity derived from expanding luciferase expressing alloreactive conventional T cells (Tconv) was significantly higher if CD30−/ − Treg as compared to wt Treg (p=0.007) were transferred as assessed by bioluminescencent based imaging. Blockade of the CD30/CD153 pathway with a neutralizing anti-CD153 mAb during the early (days −2 to +4) but not late (days +4 to +10) phase of adoptive Treg transfer reduced Treg mediated protection from proinflammatory cytokine accumulation and apoptosis of donor-type CD4 and CD8 T cells. In vivo bioluminescence imaging demonstrated intact Treg homing, but reduced expansion when CD153 was blocked during the early phase after adoptive transfer. CD30 surface expression on Treg increased with alloantigen exposure and CD153 expression on recipient-type dendritic cells increased in the presence of an irradiation induced proinflammatory environment but not when T cell depleted bone marrow and Tconv were transferred into non-irradiated Rag 2−/ −γc−/ − recipients. These data are the first to demonstrate that early CD30 signaling is relevant for Treg mediated aGvHD protection after major MHC mismatch bone marrow transplantation.

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Donor T cell–derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation

Blood ◽

10.1182/blood-2002-07-2109 ◽

2003 ◽

Vol 101 (6) ◽

pp. 2440-2445 ◽

Cited By ~ 104

Author(s):

Cornelius Schmaltz ◽

Onder Alpdogan ◽

Stephanie J. Muriglan ◽

Barry J. Kappel ◽

Jimmy A. Rotolo ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

T Cell ◽

Graft Versus Host Disease ◽

Marrow Transplantation ◽

F1 Hybrid ◽

Host Disease ◽

Graft Versus Host

Previous studies in murine bone marrow transplantation (BMT) models using neutralizing anti-tumor necrosis factor (TNF) antibodies or TNF receptor (TNFR)–deficient recipients have demonstrated that TNF can be involved in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). TNF in these GVHD and GVL models was thought to be primarily produced by activated monocytes and macrophages, and the role of T cell–derived TNF was not determined. We used TNF−/− mice to study the specific role of TNF produced by donor T cells in a well-established parent-into-F1 hybrid model (C57BL/6J→C3FeB6F1/J). Recipients of TNF−/− T cells developed significantly less morbidity and mortality from GVHD than recipients of wild-type (wt) T cells. Histology of GVHD target organs revealed significantly less damage in thymus, small bowel, and large bowel, but not in liver or skin tissues from recipients of TNF−/− T cells. Recipients of TNF−/−T cells which were also inoculated with leukemia cells at the time of BMT showed increased mortality from leukemia when compared with recipients of wt cells. We found that TNF−/− T cells do not have intrinsic defects in vitro or in vivo in proliferation, IFN-γ production, or alloactivation. We could not detect TNF in the serum of our transplant recipients, suggesting that T cells contribute to GVHD and GVL via membrane-bound or locally released TNF.

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