Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of CTLA4Ig in blocking immune activation and allograft rejection (AR) was tested in an aggressive and rapid model of rat lung AR (Brown Norway [BN]-->Lewis [LEW]). CTLA4Ig is a recombinant soluble protein that binds with high affinity to rat B7/BB1 and other surface molecules on APCs, subsequently blocking the binding of B7/BB1 to CD28/CTLA4 on T cells. This interrupts the costimulatory pathway critical for complete T cell activation and completion of the AR process. Left single-lung transplants were performed between BN-->Lew. Five allograft recipients were examined in each group. At transplantation, animals received 250 micrograms of CTLA4Ig or 250 micrograms of control Ig intraperitoneally daily until sacrifice. Animals were sacrificed on days 2, 4, and 7 after transplant. Control (BN-->Lew) grafts show irreversible rejection by day 7. Syngeneic (Lew-->Lew) grafts show no AR on day 7. AR episodes were graded histologically (stages 0-IV) and pathologic intensity of inflammation was graded on percentage of involvement. Cytokine transcript levels were measured in control and CTLA4Ig-treated animals (n = 5 in each group) on day 7 using reverse transcriptase polymerase chain reaction techniques. The most profound differences were found on day 7 after transplant. The degree of lymphocytic infiltration was greater in the CTLA4Ig group (perivascular: 4 +/- 0 vs. 2.6 +/- 0.6, peribronchial: 4 +/- 0 vs. 2.2 +/- 0.4, and peribronchiolar: 3.6 +/- 0.5 vs. 2 +/- 0.3, P < 0.01). However, in striking contrast, the stage of AR (3 +/- 0 vs. 4 +/- 0, P < 0.01), vasculitis (1 +/- 0.7 vs. 2.6 +/- 0.6, P < 0.05), hemorrhage (0.4 +/- 0.6 vs. 3.2 +/- 0.4, P < 0.01), and necrosis (0 +/- 0 vs. 2.4 +/- 0.5, P < 0.005) were significantly reduced in animals treated with CTLA4Ig. Since CTLA4Ig blocks Th1 cell activation in vitro, we compared the levels of Th1 inflammatory cytokines IL-2, gamma-IFN, and TNF-alpha in the two models. The intragraft ratios (CTLA4Ig/control) were IL-2:0.77, gamma-IFN: 1.29, and TNF-alpha:1.33. Thus, CTLA4Ig did not significantly block intragraft production of Th1 cytokines on day 7.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Soluble CTLA4Ig modifies parameters of acute inflammation in rat lung allograft rejection without altering lymphocytic infiltration or transcription of key cytokines. 753 46

Vascular endothelial cell (EC) costimulation of cytokine secretion by T lymphocytes may be important in inflammation and allograft rejection. Venous and arterial iliac endothelial cells (VIEC, AIEC) both costimulate interleukin-2 (IL-2) production by peripheral blood lymphocytes (PBL) or T cell clones stimulated with phytohemagglutinin (PHA). Interferon-gamma (IFN-gamma) production is costimulated in a subset of clones but IL-4 is not. Surprisingly, two T cell clones were reciprocally better costimulated by VIEC or AIEC. EC activation by pretreatment with tumor necrosis factor alpha (TNF-alpha) does not increase T cell costimulation despite large increases in EC cell adhesion molecule expression. Neither VIEC nor AIEC express CTLA4-binding molecules and costimulation is blocked by cyclosporin A, suggesting that CD28 is not involved in EC costimulation of T cells. These data suggest that adult vascular EC costimulate production of IL-2 and IFN-gamma but not IL-4 by mature T cells, that EC costimulation is not increased in inflamed tissues, and that different EC optimally costimulate particular T cells. These findings have implications for the nature of the costimulatory signal(s) provided by EC and may be important in understanding vasculitis or atherosclerosis.
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PMID:Arterial and venular endothelial cell costimulation of cytokine secretion by human T cell clones. 958 6

Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.
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PMID:Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice. 1168 May 72

T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.
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PMID:Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. 1844 90

Recent experimental and genetic studies have implicated the role of programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PDL-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in the pathogenesis of medium and large vessel vasculitis. This study sought to evaluate the occurrence and nature of vasculitis associated with cancer treatment using immune checkpoint inhibition (anti-PD-1, anti-PDL-1, and anti-CTLA4). A systematic review of the medical literature was conducted by searching all available clinical data up to February 2018 in several databases and search engines including Cochrane Library, Embase, Google Scholar, Medline, Scopus, Web of Science, and Clinicaltrials.gov . Searches included the following FDA-approved anti-PD1 (nivolumab and pembrolizumab), anti-PDL1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA4 (ipilimumab). The vasculitis cases were compiled and classified based on the 2012 revised Chapel Hill Consensus Conference nomenclature. The clinical feature of the vasculitis cases and their relationship to immune checkpoint inhibition was assessed. There were 53 cases of vasculitis of which 20 were confirmed. The main reported type of vasculitis was large vessel vasculitis and vasculitis of the central and peripheral nervous system. All cases resolved with either holding the immune checkpoint inhibitors and/or administering glucocorticoids. No death related to vasculitis was reported. Vasculitis, namely large vessel and vasculitis of the nervous system, is associated with immune checkpoint inhibition. Results of this study add to the growing evidence regarding the relationship between immune checkpoints and vasculitis and suggest that the pathway may be a therapeutic target.
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PMID:Vasculitis associated with immune checkpoint inhibitors-a systematic review. 2992 81

Checkpoint inhibition has become an important target in the management of malignant melanoma. As anti-CTLA4 inhibitors and anti-PD1 antibodies are increasingly utilized, reports of immune-related adverse events (IRAEs) are becoming more frequent. Common noted cutaneous IRAEs are morbilliform, lichenoid, bullous, granulomatous, psoriasiform, and eczematous eruptions. We report a case of interstitial granulomatous dermatitis and granulomatous arteritis in the setting of nivolumab (anti-PD1) monotherapy for metastatic melanoma. There are many different causes for granulomatous vasculitis, such as herpes virus infection, lymphoproliferative disorders, systemic vasculitis, and inflammatory bowel disease. This report adds to the growing literature on granulomatous IRAEs due to checkpoint inhibition.
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PMID:Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma. 3139 71

Granulomatosis with polyangiitis (GPA) is a rare and systemic autoimmune disease, causing necrotizing vasculitis of small arteries and veins. The majority of diagnosed patients with GPA have circulating antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3). Here, we have reviewed the last findings and uncertainties regarding treatments of GPA. Between the available treatments in addition to corticosteroids, cyclophosphamide (CYP) is effective for remission-induction, while it is associated with some serious side effects, such as infertility and increased risk of malignancies. On the other side, rituximab (RTX) seems a safer alternative option and as effective as CYP. It could be used as both remission-induction and maintenance therapy in GPA patients, especially in women of childbearing age. Pregnant patients, who must not be exposed to the CYP and RTX could be well-managed with intravenous immunoglobulin (IVIg). Co-trimoxazole, which is widely used to treat certain bacterial infections or as prophylaxis in immunosuppressed patients could be effective in preventing disease relapse. In the meantime, 15-deoxyspergualin, plasma exchange are other therapeutic options with a low level of evidence. Regarding potential treatments, ofatumumab, ocrelizumab, belimumab, atacicept, tabalumab, abatacept (CTLA4-Ig), and Janus kinase inhibitors seem to be effective. Renal involvement, older age, the presence of baseline organ damage, delayed-diagnosis of disease, rising in creatinine level, and higher neutrophil/lymphocyte ratio is associated with poor outcomes. Optimum doses of medications, prediction of treatment response and disease relapse, explaining lack of response in some patients, treating children with GPA, and management of GPA during the pregnancy are controversial issues, which need further studies.
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PMID:Current understanding and unknown aspects of the treatment of granulomatosis with polyangiitis (Wegener's granulomatosis): Opportunities for future studies. 3222 25