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. 2023 Aug:121:110437.
doi: 10.1016/j.intimp.2023.110437. Epub 2023 Jun 11.

Withaferin-A alleviates acute graft versus host disease without compromising graft versus leukemia effect

Saurabh Kumar Gupta  1 , Dievya Gohil  1 , Deepshikha Dutta  2 , Girish Ch Panigrahi  1 , Puja Gupta  3 , Kajal Dalvi  4 , Twinkle Khanka  4 , Subhash Yadav  5 , Rajiv Kumar Kaushal  5 , Akanksha Chichra  6 , Sachin Punatar  6 , Anant Gokarn  6 , Sumeet Mirgh  6 , Nishant Jindal  6 , Lingaraj Nayak  6 , Prashant R Tembhare  7 , Syed Khizer Hasan  2 , Santosh Kumar Sandur  8 , Lal Hingorani  9 , Navin Khattry  6 , Vikram Gota  10
Affiliations

Withaferin-A alleviates acute graft versus host disease without compromising graft versus leukemia effect

Saurabh Kumar Gupta et al. Int Immunopharmacol. 2023 Aug.

Abstract

Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from Withania somnifera (Ashwagandha), is known to have anti-inflammatory, anti-proliferative and immunomodulatory properties. The efficacy of WA for the prevention and treatment of aGvHD was evaluated using a murine model of alloHSCT. Prophylactic administration of WA to mice mitigated the clinical symptoms of aGvHD and improved survival significantly compared to the GvHD control [HR = 0.07 (0.01-0.35); P < 0.001]. Furthermore, WA group had better overall survival compared to standard prophylactic regimen of CSA + MTX [HR = 0.19 (0.03-1.1), P < 0.05]. At the same time, WA did not compromise the beneficial GvL effect. In addition, WA administered to animals after the onset of aGvHD could reverse the clinical severity and improved survival, thus establishing its therapeutic potential. Our findings suggest that WA reduced the systemic levels of Th1, Th2 and Th17 inflammatory cytokine and increased the anti-inflammatory cytokine IL-10 levels significantly (P < 0.05). WA also inhibited lymphocytes migration to gut, liver, skin and lung and protected these organs from damage. Ex-vivo, WA inhibited proliferation of human peripheral blood mononuclear cells (hPBMCs), modulated immune cell phenotype and decreased cytokine release. In addition, WA inhibited pJAK2 and pSTAT3 protein levels in mouse splenocytes and hPBMCs. In conclusion, our study demonstrates the utility of WA for the prevention and treatment of aGvHD, which should be further evaluated in a clinical setting.

Keywords: Acute graft versus host disease (aGvHD); Allogeneic hematopoietic stem cell transplantation (alloHSCT); Graft versus Leukemia (GvL); JAK2-STAT3 signaling; Prophylaxis; Treatment; Withaferin-A (WA).

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Dr. Lal Hingorani is the managing director of Pharmza Herbal Pvt. Ltd., which manufactures Witahferin-A containing nutraceuticals for human use. He had no role in the design or conduct of the study nor in the interpretation of results. Other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.’