CCR7 As a New Biomarker in Graft-Versus-Host Disease: T Cells Expressing the Homing Receptor CCR7 Mediate the Pathogenesis of Gvhd

Introduction: Graft-versus-host disease (GVHD) represents a major complication associated with allogeneic stem cell transplantation (SCT). The pathogenesis involves migration of donor naïve T cells into recipient secondary lymphoid organs. Two molecules are important in this process: CD62L and CCR7, which are characteristically expressed in naïve/central memory T cells. CD62L or L-selectin, is an adhesion molecule involved in the early phases of the lymphocyte rolling in the extravasation process. CCR7 is a chemokine receptor that binds to chemokines CCL19 or CCL21, which leads to the integrins on the lymphocytes to change from a low to a high affinity status to get a firm arrest.

Methods: This single center study included 81 donor-recipient pairs. Samples from the apheresis product were collected prospectively and phenotyped by flow cytometry (CD45, CD3, CD8, CD4, CD62L, CCR7). CD62L and CCR7 expression in T cells were compared between patients who developed acute GVHD (n=35) or chronic GVHD (n=40) and those who did not (n=35). An univariate and a multivariate analysis to search T cell subpopulations and clinical variables associated with the development of GVHD were carried out.

Results: Our data demonstrated that the acute GVHD group received a higher percentage of CCR7+CD4+ (p=0.06) compared to the no GVHD group. These results were confirmed when the patients with acute GVHD were divided in degrees according to the severity of the disease. The higher percentage of CCR7+ T cells, the more severe disease (No aGVHD vs grade I vs grade II vs grade III vs grade IV, p=0.029). Regarding chronic GVHD, significantly higher percentage of CCR7+ CD8+ (p=0.006) and CD62L+ CCR7+ CD8+ T cells (p=0.09) was observed in those patients who developed chronic GVHD in comparison to those who did not. These data were also confirmed when patients were subdivided in degrees of the disease severity. Those patients who will develop a more severe chronic GVHD were transplanted with a higher percentage of CCR7+CD8+ T cells (No cGVHD vs mild vs moderate vs severe, p=0.006). Moreover, a multivariate analysis confirmed the association between these T cell subpopulations and the development of GVHD (CCR7+CD4+ OR=1.1 [1.01-1.21]; CCR7+CD8+ OR=1.3 [1.07-1.58]) whereas no association with the classical clinical GVHD predictors studied was observed (donors´ and recipients´ age, CMV serology, HLA status, donor type, gender matching, diagnosis of the underlying disease, source of graft, number of CD3/CD34 infused, disease relapse, conditioning regimen and GVHD prophylaxis).

Conclusions: Our prospective study shows that the more percentage of CCR7+ T cells in the apheresis, the more probability of developing GVHD, indicating that alloreactive cells in the graft predominate within the naïve/central memory T cells. Therefore, we propose CCR7 as a new biomarker in the pathogenesis of GVHD that could be useful to evaluate the risk of developing this complication. Further, we also propose a selective CCR7+ T-cell depletion aiming to prevent GVHD.