Abstract
Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8+ T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.
Highlights
Allogeneic hematopoietic cell transplantation has proven as a curative therapy for life-threatening diseases of the hematopoietic system such as leukemia and lymphomas [1, 2]
We identified a combination of homing receptors, namely a4b7 integrin, CD162E, CD162P, and CD62L, on peripheral blood (PB) CD8+ T-cells that may serve as an early potential biomarker panel to predict onset of Acute graft-versus-host disease (aGvHD)
We tested an extended panel of surface markers consisting of adhesion molecules, chemokine receptors, and activation markers to determine potential biomarkers that may define alloreactive T-cells in the PB
Summary
Allogeneic hematopoietic cell transplantation (allo-HCT) has proven as a curative therapy for life-threatening diseases of the hematopoietic system such as leukemia and lymphomas [1, 2]. Acute graft-versus-host disease (aGvHD) remains the leading cause of death of transplant-related complications resulting in up to 20% mortality after allo-HCT [3, 4]. As early prediction of aGvHD remains difficult, potent preemptive immunosuppressive regimens have been established that require swift adaptation as soon as first clinical aGvHD symptoms appear. Considering the occurrence of aGvHD as an end-result of a forceful and highly dynamic immune response may explain how difficult it is to treat patients once aGvHD occurs. Naïve donor T-cells migrate to secondary lymphoid organs (SLOs), undergo allo-antigen priming, proliferate, differentiate into effector T-cells, and migrate from these priming sites to peripheral tissues such as the intestinal tract, liver, and skin, where they cause organ damage resulting in clinical aGvHD manifestation [10,11,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
