Adverse impact of a high CD4/CD8 ratio in the allograft may be overcome by methotrexate 2023

pattismith

Senior Member
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Adverse impact of a high CD4/CD8 ratio in the allograft may be overcome by methotrexate​

- but not mycophenolate- or post-transplant cyclophosphamide-based graft versus host disease prophylaxis​

Abstract​

Introduction​

A high CD4/CD8 T cell ratio in hematopoietic stem cell transplant (HSCT) allografts was observed to predict graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) but has not been comparatively examined in settings of various GVHD-prophylaxis regimens.

......​

Conclusion​

A high CD4/CD8 ratio in the allograft has an adverse impact on GVHD and survival in CSA/MMF- and PTCy-based HSCT, while MTX-based prophylaxis may largely alleviate this important risk factor.

https://onlinelibrary.wiley.com/doi/full/10.1111/ejh.13956
 

pattismith

Senior Member
Messages
3,988
This interesting effect of methotrexate may be related to the protective effect of methotrexate against cytotoxic CD4 and the promotion of CD4 T Helper

TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis 2023​


Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA);

however, its precise mechanisms of action other than antifolate activity are largely unknown.

We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment.


TAp63, an isoform of TP63, was highly expressed in human IL-17–producing Th (Th17) cells and was suppressed by MTX in vitro.

Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model.

RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene.

TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells.

Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells.

Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer.

Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.
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https://insight.jci.org/articles/view/164778
 
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