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

Gupta, Saurabh Kumar; Gohil, Dievya; Dutta, Deepshikha; Panigrahi, Girish Ch.; Gupta, Puja; Dalvi, Kajal; Khanka, Twinkle; Yadav, Subhash; Kaushal, Rajiv Kumar; Chichra, Akanksha; Punatar, Sachin; Gokarn, Anant; Mirgh, Sumeet; Jindal, Nishant; Nayak, Lingaraj; Tembhare, Prashant; Hasan, Syed Khizer; Sandur, Santosh K.; Hingorani, Lal; Nayak, Lingaraj; Gota, Vikram

doi:10.1016/j.intimp.2023.110437

Cited by 2 publications

(11 citation statements)

References 38 publications

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“…Development of aGvHD model was carried out according to the previously published study by our group 13 . Briefly, aGvHD was induced by performing allogeneic transplantation between donor C57BL/6 (H-2K b ) and recipient BALB/c (H-2K d ) mice.…”

Section: Methodsmentioning

confidence: 99%

“…After transplantation, all mice were closely monitored for aGvHD symptoms and the clinical score (CS) of aGvHD was recorded based on the following six criteria: fur texture, skin integrity, posture, activity, weight loss, and diarrhea. Clinical scoring method was adopted from Lai et al 15 and an earlier published report by our group 13 .…”

Section: Methodsmentioning

confidence: 99%

“…WSE was administered prophylactically to groups 3 and 4 at a dose of 75 mg/kg. The GvL effect was monitored according to earlier published method 13 , 16 , 17 . Leukemic death was defined by the presence of hind leg paralysis and the presence of tumor nodules in the liver.…”

Section: Methodsmentioning

confidence: 99%

“…The presence of donor-positive cell (H-2K b ) in recipient mice were evaluated as per earlier published method 13 . Briefly, peripheral blood was collected from recipient mice through retro-orbital puncture.…”

Section: Methodsmentioning

confidence: 99%

“…In recent years, many plant products such as curcumin 7 , extract of Tripterygium hypoglaucum 8 , green tea catechin epigallocatechin gallate 9 , and polyphenolic extract from olive oil 10 , have been tested against aGvHD in preclinical models due to their anti-inflammatory and immunomodulatory efficiency. Withania somnifera (Indian ginseng or Ashwagandha) also has anti-inflammatory, immune-modulatory, and antiproliferative properties 11 – 13 . The use of Withania somnifera for aGvHD, a condition orchestrated by an inflammatory milieu and a hyperactive immune response 14 , is therefore appealing.…”

Section: Introductionmentioning

confidence: 99%

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Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Gupta,

Gohil,

Momin

et al. 2024

Cell Transplant

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Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Gupta,

Gohil,

Momin

et al. 2024

Cell Transplant

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

Gohil,

Gandhi,

Gupta

et al. 2024

British J Pharmacology

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Background and PurposeAcute 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 ApproachImmunomodulatory 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 ResultsJuglone 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 ImplicationsJuglone 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.

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

Cited by 2 publications

References 38 publications

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

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

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