Suppression of alloreactivity with γδ T-cells: relevance to increased γδ T-cells following bone marrow transplantation

AbstractWe report the outcomes of 24 patients with high-risk hematologic malignancies or bone marrow failure (BMF) who received haploidentical bone marrow transplantation (BMT) after ex vivo induction of alloantigen-specific anergy in donor T cells by allostimulation in the presence of costimulatory blockade. Ninety-five percent of evaluable patients engrafted and achieved full donor chimerism. Despite receiving a median T-cell dose of 29 ×106/kg, only 5 of 21 evaluable patients developed grade C (n = 4) or D (n = 1) acute graft-versus-host disease (GVHD), with only one attributable death. Twelve patients died from treatment-related mortality (TRM). Patients reconstituted T-cell subsets and immunoglobulin levels rapidly with evidence of in vivo expansion of pathogen-specific T cells in the early posttransplantation period. Five patients reactivated cytomegalovirus (CMV), only one of whom required extended antiviral treatment. No deaths were attributable to CMV or other viral infections. Only 1 of 12 evaluable patients developed chronic GVHD. Eight patients survive disease-free with normal performance scores (median follow-up, 7 years). Thus, despite significant early TRM, ex vivo alloanergization can support administration of large numbers of haploidentical donor T cells, resulting in rapid immune reconstitution with very few viral infections. Surviving patients have excellent performance status and a low rate of chronic GVHD.

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Evidence for extrathymic generation of intermediate T cell receptor cells in the liver revealed in thymectomized, irradiated mice subjected to bone marrow transplantation.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.759 ◽

1995 ◽

Vol 182 (3) ◽

pp. 759-767 ◽

Cited By ~ 150

Author(s):

K Sato ◽

K Ohtsuka ◽

K Hasegawa ◽

S Yamagiwa ◽

H Watanabe ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

T Cell ◽

T Cell Receptor ◽

Marrow Transplantation ◽

Interleukin 2 ◽

Cell Receptor ◽

Phenotypic Characterization ◽

Receptor Cells

In addition to the major intrathymic pathway of T cell differentiation, extrathymic pathways of such differentiation have been shown to exist in the liver and intestine. In particular, hepatic T cells of T cell receptors or CD3 of intermediate levels (i.e., intermediate T cell receptor cells) always contain self-reactive clones and sometimes appear at other sites, including the target tissues in autoimmune diseases and the tumor sites in malignancies. To prove their extrathymic origin and self reactivity, in this study we used thymectomized, irradiated (B6 x C3H/He) F1 mice subjected to transplantation of bone marrow cells of B6 mice. It was clearly demonstrated that all T cells generated under athymic conditions in the peripheral immune organs are intermediate CD3 cells. In the case of nonthymectomized irradiated mice, not only intermediate CD3 cells but also high CD3 cells were generated. Phenotypic characterization showed that newly generated intermediate CD3 cells were unique (e.g., interleukin 2 receptor alpha-/beta+ and CD44+ L-selectin-) and were, therefore, distinguishable from thymus-derived T cells. The precursor cells of intermediate CD3 cells in the bone marrow were Thy-1+ CD3-. The extrathymic generation of intermediate CD3 cells was confirmed in other combinations of bone marrow transplantation, C3H --> C3H and B10.Thy1.1 --> B6.Thy1.2. The generated intermediate CD3 cells in the liver contained high levels of self-reactive clones estimated by anti-V beta monoclonal antibodies in conjunction with the endogenous superantigen minor lymphocyte-stimulating system, especially the combination of B6 --> (B6 x C3H/He) (graft-versus-host-situation).(ABSTRACT TRUNCATED AT 250 WORDS)

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Cytogenetic analysis of chimerism and leukemia relapse in chronic myelogenous leukemia patients after T cell-depleted bone marrow transplantation

Blood ◽

10.1182/blood.v75.6.1346.bloodjournal7561346 ◽

1990 ◽

Vol 75 (6) ◽

pp. 1346-1355

Author(s):

K Offit ◽

JP Burns ◽

I Cunningham ◽

SC Jhanwar ◽

P Black ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

T Cell ◽

Marrow Transplantation ◽

Myelogenous Leukemia ◽

Host Cells ◽

Clinical Relapse ◽

Cytogenetic Studies ◽

Ph Chromosome

Serial cytogenetic studies were performed on 64 patients with chronic myelogenous leukemia (CML) after T cell-depleted allogeneic bone marrow transplantation (BMT). Forty patients with CML in chronic phase (CP) received cytoreduction followed by BMT with HLA-matched T cell-depleted allogeneic marrow. The remaining 24 patients were transplanted in second chronic, accelerated, or blastic phase, or received T cell- depleted grafts with a dose of T cells added back. The Y chromosome and autosomal heteromorphisms were used to distinguish between donor and host cells. Mixed hematopoietic chimerism (presence of donor and host cells) was identified in 90% of patients in first CP. The Philadelphia (Ph) chromosome reappeared in 16 of the 40 first CP CML patients. As expected, patients who had detectable Ph chromosome positive cells at any time during the posttransplant period had a high likelihood of subsequent clinical relapse. Transient disappearance of the Ph positive clone was rarely observed, and was followed by reappearance of the Ph chromosome or clinical relapse. A subset of engrafted patients with greater than 25% host cells within 3 months post-BMT had a significantly shorter survival time free of cytogenetic or clinical relapse compared with other patients. In patients who had received donor T cells added to the T cell-depleted graft, there was a higher proportion of complete chimerism. Clonal progression of Ph positive as well as negative cells was observed and may be the result of radiation induced breakage. Serial cytogenetic studies of patients post-BMT can provide useful information regarding the biologic and clinical behavior of CML.

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Allogeneic bone marrow transplantation with a fixed low number of T- cells in the marrow graft [letter; comment]

Blood ◽

10.1182/blood.v84.10.3597.bloodjournal84103597 ◽

1994 ◽

Vol 84 (10) ◽

pp. 3597-3598

Author(s):

P Jacobs

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone Marrow ◽

Allogeneic Bone ◽

Marrow Graft ◽

Letter Comment

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Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Blood ◽

10.1182/blood-2011-12-396119 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5898-5908 ◽

Cited By ~ 79

Author(s):

Renee J. Robb ◽

Katie E. Lineburg ◽

Rachel D. Kuns ◽

Yana A. Wilson ◽

Neil C. Raffelt ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

Regulatory T Cells ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Class I ◽

Allogeneic Bone ◽

Mesenteric Lymph Nodes

Abstract FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation.

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