Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Askew, David; Pareek, Tej K.; Eid, Saada; Ganguly, Sudipto; Tyler, Megan; Huang, Alex Y.; Letterio, John J.; Cooke, Kenneth R.

doi:10.1182/blood-2016-05-702738

Cited by 16 publications

(29 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Donor T cells derived from CD62L gene-knockout mice failed to migrate to peripheral lymph nodes to recipients, thus could not induce aGVHD after transplantation [ 24 ]. Lack of CCR7 on T cells induced less SLOs entry can attenuate aGVHD severity [ 25 , 26 ]. Given that, Fluvastatin-induced increase of T cell homing might be potentially unfavorable in aGVHD, which seemed to be contradicting with the observation of reduced injury-related aGVHD in our report.…”

Section: Discussionmentioning

confidence: 99%

Fluvastatin-Pretreated Donor Cells Attenuated Murine aGVHD by Balancing Effector T Cell Distribution and Function under the Regulation of KLF2

Zhao

Tian

Wang

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still to be explored. Statins are potent immunomodulatory agents that hold promise as novel and safe agents for aGVHD prophylaxis, yet the controversial effect and regulatory mechanism are incompletely understood. Here, in an MHC mismatched murine model, we found that Fluvastatin-pretreated donor cells could attenuate aGVHD severity by remission tissue pathological injury. Fluvastatin served to restrain effector T cells entry into aGVHD target organs from secondary lymphoid organs (SLOs). The potential mechanism of correcting the effector T cell biased distribution was that Fluvastatin elevated CD62L and CCR7 expression while decreased CXCR3 and CD44 levels, which were correlated with Kruppel-like factor 2 (KLF2) sustention in donor-derived cells. In addition, Fluvastatin was contributed to reducing cytokines IFN-γ, TNF-α, and granzyme-B production in allogeneic effector CD4+ and CD8+ T cells. Furthermore, evidence confirmed that Fluvastatin had a long-lasting effect to sustain KLF2 expression both in vitro and in vivo even under the stimulated circumstance. In conclusion, administration of Fluvastatin to donor mice showed protective effects against recipient aGVHD when compared to untreated mice due to the retention of effector T cells in lymphoid organs accompanying with reduction of nonlymphatic infiltration and related inflammatory cytokines.

show abstract

Section: Discussionmentioning

confidence: 99%

Fluvastatin-Pretreated Donor Cells Attenuated Murine aGVHD by Balancing Effector T Cell Distribution and Function under the Regulation of KLF2

Zhao

Tian

Wang

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Mice received allo-BMT as previously described. 20,24,25 In studies using the B6 ! BM1 system (isolated major histocompatibility complex [MHC] class I mismatch), recipient mice received 13 Gy Total Body Irradiation (TBI) followed by the infusion of 5 Â 10 6 BM and 1.8 Â 10 6 to 2.0 Â 10 6 autoMACS-purified (>85% purity) CD8+ T cells.…”

Section: Murine Experiments and Assessment Of Gvhd Severitymentioning

confidence: 99%

Human Multipotent Adult Progenitor Cells Effectively Reduce Graft-vs-Host Disease While Preserving Graft-Vs-Leukemia Activity

et al. 2021

Self Cite

View full text Add to dashboard Cite

Graft-vs-host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo-BMT). We examined whether the administration of human, bone marrow-derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity of MAPC cells was evaluated in vivo using established murine GvHD models. Injection of MAPC cells on day +1 (D1) and +4 (D4) significantly reduced T-cell expansion and the numbers of donor-derived, Tumor Necrosis Factor Alpha (TNFα) and Interferon Gamma (IFNγ)-producing, CD4+ and CD8+ cells by D10 compared with untreated controls. These findings were associated with reductions in serum levels of TNFα and IFNγ, intestinal and hepatic inflammation and systemic GvHD as measured by survival and clinical score. Biodistribution studies showed that MAPC cells tracked from the lung and to the liver, spleen, and mesenteric nodes within 24 hours after injection. MAPC cells inhibited mouse T-cell proliferation in vitro and this effect was associated with reduced T-cell activation and inflammatory cytokine secretion and robust increases in the concentrations of Prostaglandin E2 (PGE2) and Transforming Growth Factor Beta (TGFβ). Indomethacin and E-prostanoid 2 (EP2) receptor antagonism both reversed while EP2 agonism restored MAPC cell-mediated in vitro T-cell suppression, confirming the role for PGE2. Furthermore, cyclo-oxygenase inhibition following allo-BMT abrogated the protective effects of MAPC cells. Importantly, MAPC cells had no effect on the generation cytotoxic T lymphocyte activity in vitro, and the administration of MAPC cells in the setting of leukemic challenge resulted in superior leukemia-free survival. Collectively, these data provide valuable information regarding the biodistribution and regulatory capacity of MAPC cells, which may inform future clinical trial design.

show abstract

“…This can be caused by the very large role of CDK5 in the activity of IL-2 and T cells in the inflammatory process. 9,14,15 Increased CDK5 activity can also cause an increase in TRPV1 activity so that influx calcium will increase and can cause hyperalgesia to allodynia 16 . This condition which can cause cox enzyme resistance by meloxicam is not effective in the treatment of chronic pain (resistance).…”

Section: Signs Of Inflammation In the Rat Hind Paw Experiencing Chronic Pain And Given Meloxicammentioning

confidence: 99%

The Role of Cdk5 and TRPV1 in Meloxicam Resistance Signal Transduction in Rat Experiencing Chronic Pain

Qorib,

Reny I’tishom,

Sudjarwo

et al. 2021

Indian Journal of Forensic Medicine & Toxicology

View full text Add to dashboard Cite

Chronic pain is a common case and become a serious problem. Chronic pain management are inconclusive. One of the common treatment option is NSAID. Treatment Failed are around 34-79% of total case. These treatment failed suspected as NSAID resistance. Treatment failed can be caused by a some molecule that make NSAID loss of efficacy. Cdk5 is one of the molecule that active in chronic pain condition. Cdk5 can increase transmembrane insertion and activate TRPV1. The aim of this research is analyzed the role of cdk5 and TRPV1 in NSAID resistance of chronic pain rat. This research used 42 rats as a subject and divided into 6 groups with random allocation method and factorial design. Meloxicam treatment was given orally every day for 7 days after rats have a chronic pain (28 days). Chronic pain induction used a CFA injection. Results : cdk5 and TRPV1 expression at the dorsal root ganglia of chronic pain groups are increase, no significant different of pain threshold and inflammation sign between treatment and no treatment groups after chronic pain occurred. Conclusion : chronic pain can induce cdk5 and TRPV1 expression, and induced by meloxicam treatment. Cdk5 and TRPV1 have a positive correlation with meloxicam resistance.

show abstract

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Abstract: Key Points Cdk5 function is required for optimal lymphocyte activation and migration following allo-HCT. Targeting Cdk5 may be a particularly attractive strategy to reduce GVHD and maintain antitumor activity.

Cited by 16 publications

References 73 publications

Fluvastatin-Pretreated Donor Cells Attenuated Murine aGVHD by Balancing Effector T Cell Distribution and Function under the Regulation of KLF2

Fluvastatin-Pretreated Donor Cells Attenuated Murine aGVHD by Balancing Effector T Cell Distribution and Function under the Regulation of KLF2

Human Multipotent Adult Progenitor Cells Effectively Reduce Graft-vs-Host Disease While Preserving Graft-Vs-Leukemia Activity

The Role of Cdk5 and TRPV1 in Meloxicam Resistance Signal Transduction in Rat Experiencing Chronic Pain

Contact Info

Product

Resources

About