CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT

Johnson, Bryon D.; Konkol, Marja C.; Truitt, Robert L.

doi:10.1053/bbmt.2002.v8.pm12434947

Cited by 90 publications

(64 citation statements)

References 28 publications

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“…Although we were unable to detect regulatory activity using in vitro assays where individual cell populations were employed at ratios present in the spleens of MC, we did observe a failure of nylon wool-passaged SC preparations from DLI recipients to induce severe GVHD in secondary, irradiated allogeneic recipients and demonstrated that T cells present within MC before DLI were predominantly responsible for this effect. Although we have not defined the specific T cell subset(s) responsible for suppression in this model, these data are consistent with the finding that postthymic, donor-derived CD25 ϩ T cells developing within allogeneic chimeras are important for restricting the development of GVHD (28,29). Nevertheless, it is important to note that even in the face of this regulatory impedance, sufficient activation, proliferation, and effector CTL differentiation occur to permit significant lymphohematopoietic GVH reactivity and antitumor responses in MC.…”

Section: Discussionsupporting

confidence: 82%

The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

Chakraverty

Flutter

Fallah-Arani

et al. 2008

The Journal of Immunology

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We have examined how the host environment influences the graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor T cells induce significant GVL when administered in large numbers to established mixed chimeras (MC). However, when using limiting numbers of T cells, we found that late transfer to MC induced less GVL than did early transfer to freshly irradiated allogeneic recipients. Late donor T cell transfer to MC was associated with marked accumulation of anti-host CD8 cells within the spleen, but delayed kinetics of differentiation, reduced expression of effector molecules including IFN-␥, impaired cytotoxicity, and higher rates of sustained apoptosis. Furthermore, in contrast to the spleen, we observed a significant delay in donor CD8 cell recruitment to the bone marrow, a key location for hematopoietic tumors. donor T cell alloreactivity can be exploited to generate a powerful anti-leukemia effect, a phenomenon termed the graft-vs-leukemia (GVL) response (1, 2). Unfortunately, under conditions in which donor T cells are transferred immediately to lethally irradiated recipients, GVL responses are often associated with the development of graft-vs-host disease (GVHD). Delaying the timing of donor T cell administration by 2-3 wk may reduce the risk of GVHD in full allogeneic chimeras and still permit the induction of GVL, but by 4 -5 wk, graft-vs-host (GVH) reactivity cannot be induced (3, 4). In sharp contrast, the GVL response remains intact when donor T cells are infused (at Ͼ8 wk) into established mixed chimeras (MC), where hematopoietic elements from both the donor and recipient are present at the time of transfer (5-7). This finding relates to the continued presence of large numbers of host hematopoietic APCs, which are required for maximal priming of donor T cells recognizing recipient class I (7) and class II (5) following MHC-mismatched transplantation.Although high numbers of donor T cells activated in MC do not cause GVHD, they do so readily upon transfer to secondary, irradiated allogeneic recipients (8). Moreover, the application of a local or systemic TLR stimulus allows such donor T cells to cause local or systemic GVHD, respectively (8). These studies indicate that donor leukocyte infusion (DLI)-derived GVH-reactive T cell populations activated in MC have no absolute, intrinsic functional defect. Rather, these and other data (9 -14) argue that extrinsic factors such as inflammation within the host environment are critical for the recruitment of activated T cells to the epithelial target tissues and hence the development of GVHD. It is still not known, however, whether antihost CTL arising in established MC or freshly irradiated allogeneic (TBI-allo) recipients are fully equivalent in terms of functional activity and their capacity to induce GVL. Potentially important differences between the two host environments include the duration of direct Ag presentation by professional APC, the levels of lymphopenia-induced proliferation, the extent of suppression m...

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Section: Discussionsupporting

confidence: 82%

The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

Chakraverty

Flutter

Fallah-Arani

et al. 2008

The Journal of Immunology

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“…[20][21][22][23]32 Indeed, it has been shown that CD4 ϩ CD25 ϩ T cells lower the incidence, and even completely suppress the development, of GVHD after major histocompatibility complex (MHC)-mismatched or even haploidentical murine SCT. [20][21][22][23]33 Importantly, the ratio of CD4 ϩ CD25 ϩ T cells to other cells in the donor graft has been shown to be predictive of GVHD risk. 21 The suppressor phenotype of CD4 ϩ CD25 ϩ T reg cells has also been shown to be preserved after ex vivo expansion and subsequent infusion into SCT recipients, providing a potential rationale for similar strategies in human SCT.…”

Section: Discussionmentioning

confidence: 99%

“…20 Other murine studies have confirmed that infusing donor-derived CD4 ϩ CD25 ϩ T cells may suppress the development of GVHD in a dose-dependent fashion after allogeneic SCT. [21][22][23] These results have led many to propose that enrichment, expansion, or both of CD4 ϩ CD25 ϩ T cells in donor grafts might similarly decrease the incidence of GVHD after SCT in humans, though this has not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

“…on May 10, 2018. by guest www.bloodjournal.org From that infusing donor-derived CD4 ϩ CD25 ϩ T cells may suppress the development of GVHD in a dose-dependent fashion after allogeneic SCT. [21][22][23] These results have led many to propose that enrichment, expansion, or both of CD4 ϩ CD25 ϩ T cells in donor grafts might similarly decrease the incidence of GVHD after SCT in humans, though this has not yet been studied.Because human SCT grafts vary in composition with respect to the numbers and functions of CD4 ϩ and CD8 ϩ T cells, including putative T reg cells, we sought to determine the association between CD4 ϩ CD25 ϩ T cells in donor grafts and the incidence of GVHD in patients who have undergone HLA-matched sibling SCT. No other studies published to date have examined the relationship between CD25 ϩ T cells within donor stem cell grafts and GVHD in patients who have undergone SCT.…”

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confidence: 99%

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CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans

Stanzani

Martins

Saliba

et al. 2004

Blood

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Graft-versus-host disease (GVHD) occurs in an unpredictable fashion after 30% to 50% of matched-related transplantations. The presence of increased frequencies of CD4 ؉ CD25 ؉ regulatory T cells in donor grafts has been shown to ameliorate GVHD after allogeneic transplantation in murine models. To determine whether a similar relationship exists in humans, we quantitated the coexpression of CD25 on CD4 ؉ and CD8 ؉ T cells within 60 donor grafts infused into matched siblings and examined GVHD incidence in the respective recipients. Recipients in whom GVHD developed received donor grafts containing significantly higher frequencies of CD4 ؉ T cells coexpressing CD25 than those who did not (median, 9.26% vs 2.22%; P ‫؍‬ .004). Frequencies of donor graft CD8 ؉ T cells coexpressing CD25 were also higher (0.65% vs 0.14%; P ‫؍‬ .002). Furthermore, transplant recipients who received grafts containing fewer CD4 ؉ CD25 ؉ and CD8 ؉ CD25 ؉ T cells were less likely to acquire acute GVHD, even though these donor-recipient pairs were similar to others with respect to relevant clinical variables. These data suggest that the coexpression of CD4 and CD25 may be insufficient to identify regulatory T cells in humans and that increased frequencies and numbers of CD25 ؉ T cells in donor grafts is associated with GVHD in transplant recipients. IntroductionAllogeneic stem cell transplantation (SCT) remains an important therapeutic modality for many patients with cancer, especially those with relapsed leukemia and lymphoma (reviewed in Champlin et al 1,2 ). Novel approaches to SCT, including the development of nonmyeloablative conditioning regimens and the use of peripheral blood stem cell grafts, have led to more rapid post-SCT engraftment and to reductions in morbidity and mortality, allowing allogeneic SCT to be applied to a wider range of patients, including the elderly and those with nonhematologic malignancies. 1,2 Although these advances and improvements in supportive care have improved the prognosis for patients who have undergone SCT in the past 2 decades, acute and chronic graft-versus-host disease (GVHD) remains a major cause of sickness and death after allogeneic SCT. 3,4 The incidence of GVHD, thought to be mediated by donor T cells recognizing major and minor histocompatibility antigens on recipient target cells, 5,6 may be reduced by serologic and molecular HLA matching of donors and recipients. Despite close molecular matching, GVHD occurs in an unpredictable fashion in 30% to 50% of patients after matched-related transplantation and in a higher fraction of patients after transplantation performed using HLA-mismatched or matched-unrelated donors. 3,4,7 Prior clinical studies have identified donor graft characteristics associated with an increased risk for GVHD in patients who have undergone SCT, including the infusion of increased numbers of total nucleated cells (TNCs), CD34 ϩ cells, or CD3 ϩ T cells. 3,4,8,9 In addition, murine transplantation models have identified cellular elements and cytokines that modulate the deve...

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“…93 These findings have been confirmed in animal models, which have shown that donor-derived CD4 þ CD25 þ immunoregulatory T cells are educated in the host thymus and induce tolerance with a concomitant reduction in GVHD. 94,95 The role of T reg infusions as DLI remains to be determined.…”

Section: Future Directionsmentioning

confidence: 99%

Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation

Loren

Porter

2007

Bone Marrow Transplant

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Allogeneic stem cell transplantation (SCT) offers the only hope for cure for many adults with acute leukemia. Unfortunately, many patients relapse and die of their disease even after transplantation. Although in some cases, allogeneic SCT is effective because the intensive conditioning therapy eradicates all malignant cells, it has long been recognized that the adoptive transfer of donor immunity plays a critically important role in the induction and maintenance of remission. Recognition of the graftversus-leukemia (GVL) effect of allogeneic SCT has prompted attempts at remission re-induction by adoptive immunotherapy with donor lymphocyte infusions (DLIs) in patients with relapsed disease after allogeneic SCT. In some cases, DLI-induced remissions are sustained and patients cured when no other treatment modality was effective. This review discusses the rationale, biology, complications and future applications of DLI in acute leukemia patients after allogeneic SCT.

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CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT

Cited by 90 publications

References 28 publications

The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans

Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation

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