Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease

Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7) T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in viv...

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Bibliographic Details
Published in:Bone marrow transplantation (Basingstoke) 2020-10, Vol.55 (10), p.1935-1945
Main Authors: Cuesta-Mateos, Carlos, Portero-Sainz, Itxaso, García-Peydró, Marina, Alcain, Juan, Fuentes, Patricia, Juárez-Sánchez, Raquel, Pérez-García, Yaiza, Mateu-Albero, Tamara, Díaz-Fernández, Paula, Vega-Piris, Lorena, Sánchez-López, Blanca A, Marcos-Jiménez, Ana, Cardeñoso, Laura, Gómez-García de Soria, Valle, Toribio, María Luisa, Muñoz-Calleja, Cecilia
Format: Article
Language:English
Subjects:
Antibodies
Apheresis
CC chemokine receptors
CCR7 protein
CD45RA antigen
Complement activation
Cytomegalovirus
Cytomegalovirus infections
Diseases
Effector cells
Graft versus host disease
Graft-versus-host reaction
Grafting
Health aspects
Health services
Hematopoietic stem cells
Immunological memory
Leukemia
Life span
Lymphocytes
Lymphocytes T
Medical research
Medicine, Experimental
Memory cells
Monoclonal antibodies
Relapse
Stem cell transplantation
Stem cells
T cells
Therapeutic targets
Transplantation
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Summary:Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7) T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7 cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7 T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naïve and central memory T cells toward CCR7 ligands and depleted target CCR7 subsets through complement activation. Both mechanisms of action spared CCR7 subsets, including effector memory and effector memory CD45RA T cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7 T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed.
ISSN:0268-3369
1476-5365
DOI:10.1038/s41409-020-0830-8