Browsing by Subject "Immunosuppressive agents"

Now showing 1 - 8 of 8
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    Autoimmune hepatitis: Current and future therapies
    (Wolters Kluwer, 2024-06-05) Reau, Nancy S.; Lammert, Craig S.; Weinberg, Ethan M.; Medicine, School of Medicine
    Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.
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    The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork
    (Elsevier, 2021) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Peng, Michael; Harris, Sherri L.; Webber, Hannah C.; Liu, Shaohui; Dixon, Stephan G.; Parekh, Priyanka H.; Martin, Elizabeth A.; Cantor, Louis B.; Fellman, Ronald L.; Godfrey, David G.; Butler, Michelle R.; Emanuel, Matthew E.; Grover, Davinder S.; Smith, Oluwatosin U.; Clark, Abbot F.; Raghunathan, Vijay Krishna; Mao, Weiming; Ophthalmology, School of Medicine
    Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.
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    The CYP3A5 genotypes of both liver transplant recipients and donors influence the time-dependent recovery of tacrolimus clearance during the early stage following transplantation
    (Wiley, 2021-10) Huang, Li; Assiri, Abdullah A.; Wen, Peihao; Zhang, Kun; Fan, Junwei; Xing, Tonghai; Liu, Yuan; Zhang, Jinyan; Wang, Zhaowen; Su, Zhaojie; Chen, Jiajia; Xiao, Yi; Wang, Rui; Na, Risi; Yuan, Liyun; Liu, Dehua; Xia, Junjie; Zhong, Lin; Liu, Wanqing; Guo, Wenzhi; Overholser, Brian R.; Peng, Zhihai; Medicine, School of Medicine
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    Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study
    (Wolters Kluwer, 2024) Shoji, Jun; Goggins, William C.; Wellen, Jason R.; Cunningham, Patrick N.; Johnston, Olwyn; Chang, Shirley S.; Solez, Kim; Santos, Vicki; Larson, Tami J.; Takeuchi, Masahiro; Wang, Xuegong; Surgery, School of Medicine
    Background: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. Methods: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. Results: Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. Conclusions: In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.
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    Mast cells mediate systemic immunosuppression induced by platelet-activating factor via histamine and cyclooxygenase-2 dependent mechanisms
    (2016-05-02) Ocaña, Jesus Alejandro; Safa, Ahmad R.; Travers, Jeffrey B.; Kaplan, Mark H.; Lu, Tao; Zhang, Jian-Ting
    Platelet-activating Factor (PAF) stimulates various cell types by the activation of the G-protein coupled PAF-receptor (PAFR). Systemic PAFR activation induces an acute pro-inflammatory response, as well as delayed systemic immunosuppressive effects in vivo. De novo enzymatic PAF synthesis and degradation are closely regulated, but oxidative stressors, such as UVB, and cigarette smoke, can generate PAF-like species via the oxidation of membrane lipids in an unregulated process. Mast cells (MCs) and the PAFR have been shown to be necessary to mediate the resulting systemic immune suppression from oxidative stressors. The work herein implicates pro-oxidative chemotherapeutics, such as melphalan and etoposide, in mediating augmentation in tumor growth by inducing the generation of PAFR agonists via the oxidation of membrane lipids. This work also demonstrates the role of MCs and MC-released mediators in PAFR systemic immunosuppression. Through a contact hypersensitivity (CHS) model, the MC PAFR was found to be necessary and sufficient for PAF to mediate systemic immunosuppression. Additionally, activation of the MC PAFR seems to induce MC histamine and prostaglandin E2 release. Furthermore, by transplanting histamine- or COX-2-deficient MCs into MC-deficient mice, MC-derived histamine and prostaglandin release were found to be necessary for PAF to induce systemic immunosuppression. Lastly, we have evidence to suggest that prostaglandin release modulates MC migration to draining lymph nodes, a process necessary to promote immunosuppression. These studies fit with the hypothesis that MC PAFR activation mediates PAFR systemic immunosuppression in part by histamine and prostaglandin release.
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    PharmVar GeneFocus: CYP3A5
    (Wiley, 2022) Rodriguez-Antona, Cristina; Savieo, Jessica L.; Lauschke, Volker M.; Sangkuhl, Katrin; Drögemöller, Britt I.; Wang, Danxin; van Schaik, Ron H. N.; Gilep, Andrei A.; Prakasam Peter, Arul; Boone, Erin C.; Ramey, Bronwyn E.; Klein, Teri E.; Whirl-Carrillo, Michelle; Pratt, Victoria M.; Gaedigk, Andrea; Medicine, School of Medicine
    The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates, including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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    The stimulatory role of ICOS in the development of CD146+CCR5+ T cells co-expressing IFN-γ and IL-17 during graft-versus-host disease
    (2015) Liu, Liangyi; Paczesny, Sophie; Broxmeyer, Hal E.; Blum, Janice S.; Haneline, Laura S.; Carlesso, Nadia
    Graft-versus-host disease (GVHD) remains the major complication after allogeneic hematopoietic stem cell transplantation (HSCT), resulting from immunological attack on target organs such as gastrointestinal (GI) tract, liver and skin from donor allogeneic T cells. The most common treatment for GVHD is immunosuppressive drugs such as corticosteroids, which may result in many side effects including the loss of the beneficial graft-versus-leukemia (GVL) effect and increased infection rates. However, GVHD-specific drugs have yet to be implemented. Here we show that by targeting on a novel pathogenic CD4+ T cell subpopulation that our lab previously found in patients with GI GVHD, we can develop new avenues to treat GVHD. This novel population is characterized as CD146+CCR5+ T cells, co-expressing IL-17A and IFN-γ. We found that the inducible T-cell costimulator (ICOS), which has been reported to be important for human Th17 differentiation in vitro, is critical for the development of this nonconventional T Helper 1 (Th1*)-polarized CD146+CCR5+ conventional T cells (Tconvs) population. Furthermore, we found that ICOS can induce the generation of Th1*-polarized CD146+CCR5+ regulatory T cells (Tregs) population, lowering the frequencies of phenotypic markers of functional Tregs. Our data also showed that inhibiting the major transcriptional factor of Th17, RAR-related orphan receptor gamma t (RORγt), could prevent the development of CD146+CCR5+ Tconvs in vitro. Our results demonstrate how pathogenic CD146+CCR5+ T cells are induced through ICOS or RORγt, suggesting new targets for GVHD treatment. We anticipate our assay to be a starting point for the development of novel GVHD-specific drugs. For example, the treatments that focus on inhibiting RORγ would have fewer side effects than general immunosuppressive drugs that GVHD patients use today and inhibit GVHD while sparing the GVL effect. Furthermore, we expect the CD146+CCR5+ Tconvs and/or Tregs can be used as GVHD biomarkers. These biomarkers may guide preemptive treatments such as RORγt inhibitor.
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    Vaccines: Considerations for pediatric dermatology patients on immunosuppressive agents
    (Wiley, 2021) Munshi, Mumtaz A.; Noe, Megan H.; Chiu, Yvonne E.; Streicher, Jenna L.; Dermatology, School of Medicine
    Pediatric dermatologists should be aware of immunization schedules and special recommendations for patients on immunosuppressive agents due to the increased risk of vaccine-preventable infections. Prior to initiating immunosuppressive therapy, pediatric dermatologists should review a vaccine history and administer any necessary age-appropriate or catch-up vaccines. Live vaccines are typically contraindicated while on immunosuppressive therapy, while inactivated vaccines are generally safe to administer.