Immunomodulation by juglone alleviates acute graft-versus-host disease without compromising the graft-versus-leukaemia activity in mice.

Autor: Gohil D; Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.; Training School Complex, Homi Bhabha National Institute, Mumbai, India., Gandhi KA; Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.; Training School Complex, Homi Bhabha National Institute, Mumbai, India., Gupta SK; Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.; Training School Complex, Homi Bhabha National Institute, Mumbai, India., Gera P; ICGC Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.; Biorepository, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India., Yadav S; Training School Complex, Homi Bhabha National Institute, Mumbai, India.; Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India., Patwardhan R; Training School Complex, Homi Bhabha National Institute, Mumbai, India.; Radiation Biology & Health Science Division, Bio-science group, Bhabha Atomic Research Centre, Mumbai, India., Checker R; Training School Complex, Homi Bhabha National Institute, Mumbai, India.; Radiation Biology & Health Science Division, Bio-science group, Bhabha Atomic Research Centre, Mumbai, India., Sharma D; Training School Complex, Homi Bhabha National Institute, Mumbai, India.; Radiation Biology & Health Science Division, Bio-science group, Bhabha Atomic Research Centre, Mumbai, India., Khattry N; Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India., Sandur S; Training School Complex, Homi Bhabha National Institute, Mumbai, India.; Radiation Biology & Health Science Division, Bio-science group, Bhabha Atomic Research Centre, Mumbai, India., Gota V; Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.; Training School Complex, Homi Bhabha National Institute, Mumbai, India.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Apr 07. Date of Electronic Publication: 2024 Apr 07.
DOI: 10.1111/bph.16350
Abstrakt: Background and Purpose: Acute graft-versus-host disease (GVHD) remains a major barrier to successful transplantation outcomes. Recent studies have shown that pharmacotherapy for GVHD should target both the innate and adaptive inflammatory immune responses. Juglone, a redox-active phytochemical found in walnuts, has shown potent anti-inflammatory effects in models of colitis and inflammatory bowel disease. However, its effects on T-cell-mediated immune responses remain largely unknown. Considering the overlapping mediators of inflammation in GVHD and the aforementioned conditions, we investigated the use of juglone as a prophylactic agent for GVHD.
Experimental Approach: Immunomodulatory activity and mechanism of action of juglone were studied using murine splenic leukocytes in vitro. The GVHD prophylactic efficacy of orally administered juglone was evaluated using a murine model of allogeneic haematopoietic stem cell transplantation based on an MHC mismatch.
Key Results: Juglone exhibited immunomodulatory activity by (i) inhibiting the activation of dendritic cells and CD4 + T-cells, (ii) inhibiting cytokine secretion and lymphocyte proliferation, and (iii) inducing exhaustion of CD4 + T-cells, as shown by increased expression of CTLA-4 (CD152) and Fas (CD95). Oral administration of juglone significantly reduced mortality and morbidity associated with GVHD while maintaining graft-versus-leukaemia activity. This was accompanied by a decrease in the number of naïve CD4 + cells, and an increase in the number of CD4 + and CD8 + central memory T-cells.
Conclusion and Implications: Juglone is a potent immunomodulator for GVHD prophylaxis. Our study is the first to provide a dosage framework for the oral administration of juglone that can be used for clinical development.
(© 2024 British Pharmacological Society.)
Databáze: MEDLINE
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