CP-690550, a Janus Kinase Inhibitor, Suppresses CD4+ T-Cell–Mediated Acute Graft-Versus-Host Disease by Inhibiting the Interferon-γ Pathway

Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell reconstitution (CD4+IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients who developed aGvHD. Pediatric patients receiving their first allogeneic HCT at the UMC Utrecht / Princess Máxima Center (UMC/PMC) or Memorial Sloan Kettering Cancer Center (MSK), were included. Primary outcomes were non-relapse mortality (NRM) and overall survival (OS), stratified for aGvHD and CD4+IR; defined as ³50 CD4+ T-cells/uL within 100 days after HCT, or prior to aGvHD onset. Multivariate and time-to-event Cox Proportional Hazard models were applied. 591 Patients (N= 276 UMC/PMC; N= 315 MSK) were included. NRM in patients with aGvHD grade III-IV with or without CD4+IR within 100 days after HCT was 30% vs 80% (p=0.02) at UMC/PMC and 5% vs 67% (p=0.02) at MSK. This associated with lower OS without CD4+IR; 61% vs. 20% (p=0.04) at UMC/PMC, and 75% vs. 33% (p=0.12) at MSK. Inadequate CD4+IR prior to aGvHD onset associates with significantly higher NRM; 74% vs 12% (p<0.001), and inferior OS; 24% vs 78% (p<0.001). In this retrospective analysis we demonstratethat early CD4+ IR, a simple and robust markerpredictive of outcomes after HCT,associates with survival after moderate to severe aGvHD.These associations need to be confirmed in a prospective manner but suggest that strategies to improve T-cell recovery after HCT may influence survival in patients developing aGvHD.

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CCR6 regulates CD4+ T-cell–mediated acute graft-versus-host disease responses

Blood ◽

10.1182/blood-2004-08-2996 ◽

2005 ◽

Vol 106 (1) ◽

pp. 18-26 ◽

Cited By ~ 61

Author(s):

Rosa Varona ◽

Vanesa Cadenas ◽

Lucio Gómez ◽

Carlos Martínez-A ◽

Gabriel Márquez

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Interleukin 10 ◽

Interferon Γ ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

We studied the role of chemokine receptor CCR6 in acute graft-versus-host disease (GvHD), a pathology in which activated, host antigen-specific donor T cells selectively damage tissues such as skin, liver, and gut. GvHD incidence was reduced in major histocompatibility complex (MHC) class II–mismatched recipients of CD4+ T cells from CCR6-deficient donors. In MHC-matched/minor histocompatibility antigen–mismatched recipients of CD4+CD45RBhigh T cells from CCR6-deficient donors, infiltration of CD45+ and CD4+ cells to skin and gut, as well as lesion onset, were significantly delayed, and pathologic symptoms were milder. Consistent with this, in skin and gut of recipients of naive T cells from CCR6-deficient donors we observed lower levels of interferon γ (IFN-γ), interleukin 10 (IL-10), and the chemokines that control activated T-cell homing. We suggest a role for CCR6 in recruiting alloreactive CD4+ T cells to target tissues and identify CCR6 as a potential therapeutic target for GvHD.

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