Browsing by Subject "Immunosuppression"
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Item Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice(Wiley, 2022) Arellano, Danna L.; Juárez, Patricia; Verdugo-Meza, Andrea; Almeida-Luna, Paloma S.; Corral-Avila, Juan A.; Drescher, Florian; Olvera, Felipe; Jiménez, Samanta; Elzey, Bennett D.; Guise, Theresa A.; Fournier, Pierrick G.J.; Medicine, School of MedicineImmunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)+ in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties.Item CCL21 Induces Plasmacytoid Dendritic Cell Migration and Activation in a Mouse Model of Glioblastoma(MDPI, 2024-10-12) Zhao, Lei; Shireman, Jack; Probelsky, Samantha; Rigg, Bailey; Wang, Xiaohu; Huff, Wei X.; Kwon, Jae H.; Dey, Mahua; Neurological Surgery, School of MedicineDendritic cells (DCs) are professional antigen-presenting cells that are traditionally divided into two distinct subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). pDCs are known for their ability to secrete large amounts of cytokine type I interferons (IFN- α). In our previous work, we have demonstrated that pDC infiltration promotes glioblastoma (GBM) tumor immunosuppression through decreased IFN-α secretion via TLR-9 signaling and increased suppressive function of regulatory T cells (Tregs) via increased IL-10 secretion, resulting in poor overall outcomes in mouse models of GBM. Further dissecting the overall mechanism of pDC-mediated GBM immunosuppression, in this study, we identified CCL21 as highly upregulated by multiple GBM cell lines, which recruit pDCs to tumor sites via CCL21-CCR7 signaling. Furthermore, pDCs are activated by CCL21 in the GBM microenvironment through intracellular signaling of β-arrestin and CIITA. Finally, we found that CCL21-treated pDCs directly suppress CD8+ T cell proliferation without affecting regulatory T cells (Tregs) differentiation, which is considered the canonical pathway of immunotolerant regulation. Taken together, our results show that pDCs play a multifaced role in GBM immunosuppression, and CCL21 could be a novel therapeutic target in GBM to overcome pDC-mediated immunosuppression.Item Clinical Outcomes of Therapeutic Interventions for Autoimmune Retinopathy: A Meta-analysis and Systematic Review(Elsevier, 2024-09-12) Kapoor, Ishani; Sarvepalli, Swara M.; Grewal, Dilraj S.; Hadziahmetovic, Majda; Ophthalmology, School of MedicineTopic: Autoimmune retinopathy (AIR) is a group of rare inflammatory diseases treated with immunosuppression; however, there is no treatment consensus. This meta-analysis and review aims to investigate treatment effectiveness in slowing AIR progression. Clinical relevance: Autoimmune retinopathy is a group of diseases characterized by progressive vision loss that is both difficult to diagnose and treat. While there is some consensus regarding diagnostic criteria, evidence-based treatment consensus remains poorly understood. Current first-line treatment is systemic steroids and conventional steroid-sparing agents. However, patients often experience treatment failure and systemic adverse effects with these medications. Understanding the effect of medications on slowing multiple visual outcomes in AIR can help to guide future treatment protocols. Methods: PubMed, Cochrane Library, Embase, and ClinicalTrials.gov were systematically searched from inception to November 2023. Included studies treated patients with AIR with systemic, local, and biologic therapy and reported visual acuity (VA), visual field (VF), cystoid macular edema (CME), electroretinogram, central retinal thickness (CRT), and/or ellipsoid zone (EZ) loss. Risk of bias was assessed using the Critical Appraisal Skills Programme checklist. Data for meta-analysis were pooled using a random-effects model. Results: Analysis of 40 case reports demonstrated that treatment type significantly affects the improvement of VA in patients with nonparaneoplastic retinopathy. Meta-analysis of 12 studies demonstrated that any treatment decreases the risk of progression of all 6 outcomes. Systemic therapy slows VA loss (risk ratio [RR] = 0.04, 95% confidence interval [0.00, 0.91], P = 0.04), VF loss (RR = 0.01, 95% confidence interval [0.00, 0.14], P = 0.0007), and CME (RR = 0.02, 95% confidence interval [0.00, 0.34], P = 0.007). Local therapy slows VA loss (RR = 0.02, 95% confidence interval [0.00, 0.12], P < 0.00001), CME (RR = 0.06, 95% confidence interval [0.01, 0.43], P = 0.005), CRT loss (RR = 0.02, 95% confidence interval [0.00, 0.36], P = 0.007), and EZ loss (RR = 0.31, 95% confidence interval [0.14, 0.70], P = 0.004). Biologics slow VA loss (RR = 0.28, 95% confidence interval [0.12, 0.65], P = 0.003), VF loss (RR = 0.25, 95% confidence interval [0.15, 0.42], P < 0.00001), and CRT loss (RR = 0.19, 95% confidence interval [0.04, 0.79], P = 0.02). Conclusion: Systemic therapy significantly reduces the risk of progressive visual loss. Local therapy significantly decreases the risk of both progressive visual loss and retinal morphology loss, and therefore may offer precise targeting of the retina. Biologics significantly reduce both functional and morphological retinal changes. Immunosuppressive therapy may slow AIR progression; however, additional research is needed to assess long-term outcomes.Item Critical Role of the mTOR Pathway in Development and Function of Myeloid-Derived Suppressor Cells in lal−/− Mice(Elsevier B.V., 2014-02) Ding, Xinchun; Du, Hong; Yoder, Mervin C.; Yan, Cong; Department of Pathology and Laboratory Medicine, IU School of MedicineLysosomal acid lipase (LAL) is essential for the hydrolysis of cholesteryl esters and triglycerides to generate cholesterol and free fatty acids in cellular lysosomes. Ablation of the lal gene (lal−/−) systemically increased expansion of cluster of differentiation molecule 11b (CD11b), lymphocyte antigen 6G (Ly6G) myeloid-derived suppressor cells (MDSCs) that caused myeloproliferative neoplasms in mice. Study of lal−/− bone marrow Ly6G+ MDSCs via transcriptional profiling showed increases in mammalian target of rapamycin (mTOR) signaling pathway transcripts. Injection of mTOR pharmacologic inhibitors into lal−/− mice significantly reduced bone marrow myelopoiesis and systemic CD11b+Ly6G+ cell expansion. Rapamycin treatment of lal−/− mice stimulated a shift from immature CD11b+Ly6G+ cells to CD11b+ single-positive cells in marrow and tissues and partially reversed the increased cell proliferation, decreased apoptosis, increased ATP synthesis, and increased cell cycling of bone marrow CD11b+Ly6G+ cells obtained from lal−/− mice. Pharmacologic and siRNA suppression of mTOR, regulatory-associated protein of mTOR, rapamycin-insensitive companion of mTOR, and Akt1 function corrected CD11b+Ly6G+ cell in lal−/− mice development from Lin− progenitor cells and reversed the immune suppression on T-cell proliferation and function in association with decreased reactive oxygen species production, and recovery from impairment of mitochondrial membrane potential compared with control mutant cells. These results indicate a crucial role of LAL-regulated mTOR signaling in the production and function of CD11b+Ly6G+ cells. The mTOR pathway may serve as a novel target to modulate the emergence of MDSCs in those pathophysiologic states in which these cells play an immunosuppressive role.Item Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation(MDPI, 2024-03-16) Chen, Can; Zhang, Ji; Pediatrics, School of MedicineCancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.Item Establishment of lal-/- myeloid lineage cell line that resembles myeloid-derived suppressive cells(PLoS, 2015-03-25) Ding, Xinchun; Wu, Lingyan; Yan, Cong; Du, Hong; Department of Pathology and Laboratory Medicine, IU School of MedicineMyeloid-derived suppressor cells (MDSCs) in mouse are inflammatory cells that play critical roles in promoting cancer growth and metastasis by directly stimulating cancer cell proliferation and suppressing immune surveillance. In order to facilitate characterization of biochemical and cellular mechanisms of MDSCs, it is urgent to establish an "MDSC-like" cell line. By cross breeding of immortomouse (simian virus 40 large T antigen transgenic mice) with wild type and lysosomal acid lipase (LAL) knock-out (lal-/-) mice, we have established a wild type (HD1A) and a lal-/- (HD1B) myeloid cell lines. Compared with HD1A cells, HD1B cells demonstrated many characteristics similar to lal-/- MDSCs. HD1B cells exhibited increased lysosomes around perinuclear areas, dysfunction of mitochondria skewing toward fission structure, damaged membrane potential, and increased ROS production. HD1B cells showed increased glycolytic metabolism during blockage of fatty acid metabolism to fuel the energy need. Similar to lal-/- MDSCs, the mTOR signal pathway in HD1B cells is overly activated. Rapamycin treatment of HD1B cells reduced ROS production and restored the mitochondrial membrane potential. HD1B cells showed much stronger immunosuppression on CD4+ T cell proliferation and function in vitro, and enhanced cancer cells proliferation. Knockdown of mTOR with siRNA reduced the HD1B cell ability to immunosuppress T cells and stimulate cancer cell proliferation. Therefore, the HD1B myeloid cell line is an "MDSC-like" cell line that can be used as an alternative in vitro system to study how LAL controls various myeloid cell functions.Item Exosomal Transfer of DNA Methyl-Transferase mRNA Induces an Immunosuppressive Phenotype in Human Monocytes(Wolters Kluwer, 2022) Wisler, Jon R.; Singh, Kanhaiya; McCarty, Adara; Harkless, Ryan; Karpurapu, Manjula; Hernandez, Edward; Mukherjee, Debasmita; Abouhashem, Ahmed S.; Christman, John W.; Sen, Chandan K.; Surgery, School of MedicineIntroduction: Survivors of sepsis exhibit persistent immunosuppression. Epigenetic events may be responsible for some of these immunosuppressive changes. During sepsis circulating exosomes contain large quantities of DNA methyltransferase (DNMT) mRNAs. We hypothesized that exosomes directly transfer DNMT mRNAs to recipient monocytes with resultant methylation events and immunosuppression. Methods: Exosomes containing DNMT mRNA were generated by stimulating monocytes with LPS. Confocal microscopy was used to determine uptake kinetics in the presence of pharmacologic inhibition. Expression and packaging of specific DNMT mRNA was controlled using DNMT siRNAs. Whole genome and gene specific methylation was assessed using bisulfite sequencing. Ingenuity pathway analysis was performed to determine the biological function of significance of differentially methylated regions. Results: Exosomes effectively transferred DNMT mRNA to recipient monocytes. Pharmacologic inhibition of exosome uptake prevented this increase in DNMT mRNA expression. Recipient monocytes exhibited hypermethylation changes and gene suppression. siRNAs decreased the packaging of DNMT mRNAs and prevented TNFα gene suppression, restoring immunocompetence. Conclusion: These data support a role for exosome-mediated transfer of DNMT mRNA with resultant methylation and gene silencing. Pharmacologic uptake inhibition or targeted siRNA mediated DNMT gene silencing prevented DNMT mRNA transfer and maintained the cell's ability to express TNFα in response to LPS. This highlights the potential therapeutic value of targeting these exosome-mediated epigenetic events to maintain the host immune response during sepsis.Item FOXP3 interacts with hnRNPF to modulate pre-mRNA alternative splicing(American Society for Biochemistry and Molecular Biology, 2018-06-29) Du, Jianguang; Wang, Qun; Ziegler, Steven F.; Zhou, Baohua; Microbiology and Immunology, School of MedicineFOXP3 promotes the development and function of regulatory T cells mainly through regulating the transcription of target genes. RNA alternative splicing has been implicated in a wide range of physiological and pathophysiological processes. We report here that FOXP3 associates with heterogeneous nuclear ribonucleoprotein (hnRNP) F through the exon 2-encoded region of FOXP3 and the second quasi-RNA recognition motif (qRRM) of hnRNPF. FOXP3 represses the ability of hnRNPF to bind to its target pre-mRNA and thus modulates RNA alternative splicing. Furthermore, overexpression of mouse hnRNPF in in vitro-differentiated regulatory T cells (Tregs) reduced their suppressive function. Thus, our studies identify a novel mechanism by which FOXP3 regulates mRNA alternative splicing to modulate the function of regulatory T cells.Item Gamma-delta mycosis fungoides in a posttransplant patient(Elsevier, 2020-03) Bitter, Julie M.; Warren, Simon; Mark, Lawrence A.; Medicine, School of MedicineMycosis fungoides (MF) is a clonal T-cell lymphoproliferative disorder of the skin that accounts for an estimated 50% to 60% of cutaneous T cell lymphoma (CTCL) cases.1,2 The gamma-delta (gd) subtype of MF (GD-MF) is a rare variant, with only a few cases reported in the literature and only 1 in a patient after solid organ transplant.3 Here we present a case of GD-MF developing after liver transplantation in an older man.Item Gastrointestinal histoplasmosis complicating pediatric Crohn disease: A case report and review of literature(Baishideng Publishing Group, 2022) Miller, C. Quinn; Saeed, Omer A.M.; Collins, Katrina; Pathology and Laboratory Medicine, School of MedicineBackground: Infection with Histoplasma capsulatum (H. capsulatum) can lead to disseminated disease involving the gastrointestinal tract presenting as diffuse abdominal pain and diarrhea which may mimic inflammatory bowel disease (IBD). Case summary: We report a case of 12-year-old boy with presumptive diagnosis of Crohn disease (CD) that presented with several months of abdominal pain, weight loss and bloody diarrhea. Colonoscopy showed patchy moderate inflammation characterized by erythema and numerous pseudopolyps involving the terminal ileum, cecum, and ascending colon. Histologic sections from the colon biopsy revealed diffuse cellular infiltrate within the lamina propria with scattered histiocytic aggregates, and occasional non-necrotizing granulomas. Grocott-Gomori's Methenamine Silver staining confirmed the presence of numerous yeast forms suggestive of Histoplasma spp., further confirmed with positive urine Histoplasma antigen (6.58 ng/mL, range 0.2-20 ng/mL) and serum immunoglobulin G antibodies to Histoplasma (35.9 EU, range 10.0-80.0 EU). Intravenous amphotericin was administered then transitioned to oral itraconazole. Follow-up computed tomography imaging showed a left lower lung nodule and mesenteric lymphadenopathy consistent with disseminated histoplasmosis infection. Conclusion: Gastrointestinal involvement with H. capsulatum with no accompanying respiratory symptoms is exceedingly rare and recognition is often delayed due to the overlapping clinical manifestations of IBD. This case illustrates the importance of excluding infectious etiologies in patients with "biopsy-proven" CD prior to initiating immunosuppressive therapies. Communication between clinicians and pathologists is crucial as blood cultures and antigen testing are key studies that should be performed in all suspected cases of histoplasmosis to avoid misdiagnosis and inappropriate treatment.