Journal
CELLULAR IMMUNOLOGY
Volume 367, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.cellimm.2021.104410
Keywords
Hematopoietic cell transplantation; Graft-versus-host disease; MEK inhibitor; Immune reconstitution; T-cell receptor (TCR) repertoire
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Funding
- MEXT KAKENHI [26461451]
- Japan Agency for Medical Research and Development research grants
- Takeda Science Foundation
- SENSHIN Medical Research Foundation
- Kobayashi Cancer Research Foundation
- Bristol-Myers Squibb Foundation
- Uehara Memorial Foundation
- Novartis Pharmaceuticals Foundation
- Kanae Foundation for the Promotion of Medical Science
- Grants-in-Aid for Scientific Research [26461451] Funding Source: KAKEN
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The MEK inhibitor trametinib ameliorates GVHD and promotes diverse T-cell clone engraftment, offering a novel rationale for translational studies targeting human GVHD compared to tacrolimus.
Rapid immune reconstitution without developing graft-versus-host disease (GVHD) is required for the success of allogeneic hematopoietic stem cell transplantation. Here, we analyzed the effects of pharmacological MEK inhibition on human polyclonal T-cell reconstitution in a humanized mouse GVHD model utilizing deep sequencing-based T-cell receptor (TCR) repertoire analysis. GVHD mice exhibited a skewed TCR repertoire with a common clone within target organs. The MEK inhibitor trametinib ameliorated GVHD and enabled engraftment of diverse T-cell clones. Furthermore, trametinib also ameliorated GVHD sparing diverse T cell repertoire, even when it was given from day 15 through 28. Although tacrolimus also reduced development of GVHD, it disturbed diverse T cell reconstitution and resulted in skewed TCR repertoire. Thus, trametinib not only suppresses GVHDinducing T cells but also promotes human T cell reconstitution in vivo, providing a novel rationale for translational studies targeting human GVHD.
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