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

Abstract

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...

Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose

“…One group reported more frequent cGVHD with higher CD34 ϩ cell dose after reduced-intensity transplantation, while others found no such association. 10,30,[38][39][40] Additionally, high CD34 ϩ cell dose was identified as an adverse predictive factor influencing survival in some instances but, again, not in others. 30,[41][42][43] We report no significant association between CD34 ϩ cell dose with clinical outcome.…”

Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells

“…It is also conceivable that as a result of thymic injury, the repertoire of T reg cells is incomplete and lacks particular specificities that would be required for the prevention of tissue injury. Conversely, T reg cells may in fact have a causative role in the development of cGVHD, a possibility that might be suggested by the finding that allogeneic peripheral blood stem cell (PBSC) grafts containing higher numbers of CD4 ϩ CD25 high T cells are associated with an increased risk of cGVHD 41 or that patients with cGVHD show responses to therapy with daclizumab, a humanized monoclonal antibody directed against human IL-2 receptor ␣ chain. 42 T reg cell-mediated suppression of individual components of the effector immune response could prevent full resolution of the inflammatory state or alternatively T reg cell induction of cytokines such as TGF-␤ could exacerbate chronic tissue injury.…”

The Graft Content of Donor T Cells Expressing γδTCR+ and CD4+foxp3+ Predicts the Risk of Acute Graft versus Host Disease after Transplantation of Allogeneic Peripheral Blood Stem Cells from Unrelated Donors

“…Tregs inhibit autoreactive T-cell proliferation and suppress B-cell responses (9), thereby mediating graft tolerance while preserving a graft-versus-malignancy effect in the clinical setting of allogeneic HSCT (10). Although there are some limited and conflicting reports on the role of Tregs after related PBSC transplantation (PBSCT) (11,12) their role after allogeneic transplantation from unrelated donors in man is unknown. Given the greater frequency of acute and chronic GVHD and treatment-related mortality (TRM) after transplants from alternative donors, there is a significant clinical need for better understanding of how Tregs interact within the host immune system.…”