A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy

Abstract

CC-chemokine receptor 7 (CCR7), a chemokine receptor required for transmigration into lymphoid organs, is only expressed by naive and central memory T cells. T cells with a capacity of homing into lymphoid organs can initiate acute graft-versus-host disease (GVHD) in mice and respond vigorously in vitro to alloantigens in humans, but their impact on clinical outcomes is unknown. We evaluated prospectively the distribution of naive, central memory and CCR7 neg memory T-cell subsets in 39 bone marrow and 23 granulocyte colonystimulating factor-mobilized peripheral blood stem cell allografts and investigated their impact on patient outcomes. Ranges of the relative proportions of CCR7 þ cells within CD4 þ and CD8 þ T-cell populations were broad, but did not differ between the two sources of allografts. By multivariate analysis, high percentage of donor-derived CD4 þ CCR7 þ T cells (473.5%) significantly correlated with incidence, earliness of onset and severity of acute GVHD, conferring the highest adjusted hazard ratio (HR ¼ 3.9; 95% confidence interval 1.4-10.8; P ¼ 0.008) without interfering in other clinical events, especially chronic GVHD and relapse. Determination of the percentage of CD4 þ CCR7 þ T cells in the graft provides a predictive indicator of acute GVHD. Partial depletion of this subset may reduce the risk of acute GVHD while preserving immunotherapeutic effects.

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

“…20 Naı¨ve, central memory and effector memory T-cell subsets were categorized within the CD4 þ and the CD8 þ pools based on the expression of CD45RA and CCchemokine receptor 7 markers. 21 The expression of IL-7Ra (CD127) and IL-2/15Rb (CD122) was evaluated in each of these subsets by determining the percentage of cells with positive staining for the receptor chain and their median fluorescence intensity.…”

Differences in proportion and dynamics of recipient hematopoiesis following hematopoietic cell transplantation in CML and IMF

“…Concerning the time-points day +100 posttransplant, however, effects of initial therapy (allo-BMT and allo-HSCT) are blurred because at that time-point the interplay between immune reactivity of the graft and immunogenity of the tumor cells is regarded to be essential for the course of the individual disease (19,34). In addition, individual ranges of the relative proportion of T-cells are indeed broad but are reported not to differ between BM and peripheral blood stem cell allografts (35).…”

In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

“…This has been underpinned by our greater understanding of the different cells that constitute the graft and their contribution to alloresponses [2]. Naïve T (T N ) cells from grafts are the major cells responsible for graft-versus-host disease (GvHD), whereas other cells, such as effector memory T (T EM ), central memory T (T CM ), and NK cells, have potential for promoting immunity and antitumor activity, respectively [1,[3][4][5][6]. In order to mitigate alloresponses by donor T N cells, current graftengineering techniques utilize ex vivo bulk T-cell depletion or positive selection of CD34 + cells.…”

“…In order to mitigate alloresponses by donor T N cells, current graftengineering techniques utilize ex vivo bulk T-cell depletion or positive selection of CD34 + cells. These techniques, however, can leave the graft devoid of useful immune cells, potentially making the recipient more susceptible to infection and relapse [1,2].Techniques specifically targeting depletion of T N cells from grafts could potentially help maximize the capacity of grafts for immune reconstitution, antitumor activity as well as prevention of GvHD in recipients [1,[3][4][5][6]. Bleakley et al have recently described a promising protocol in which T N cells are depleted from mobilized grafts, but this still requires ex vivo manipulation of grafts and complex selection strategies [7].…”