DURING the past decade a wealth of information concerning the pathogenesis of Type I diabetes has become available. Two spontaneous animal models of the disease have been discovered and characteriz...

Type I diabetes mellitus. A chronic autoimmune disease.

Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

https://science.sciencemag.org/content/sci/226/4674/544.full.pdf

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

Background Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease. Methods We studied the effects of a nonactivating humanized monoclonal antibody against CD3 — hOKT3γ1(Ala-Ala) — on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease. Results Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls ...

Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus

Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.

Genetics, pathogenesis and clinical interventions in type 1 diabetes

We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

Cyclosporine-associated chronic nephropathy

Effects of cyclosporine in recent-onset juvenile type 1 diabetes: Impact of age and duration of disease

<h3>Background</h3> V-domain immunoglobulin suppressor of T cell activation (VISTA) is a negative checkpoint regulator of immune cells. VISTA has been recognized as a potential mediator of resistance to anti-PD-1 and anti-CTLA-4 immunotherapies in cancer patients. Targeting the VISTA signaling pathway has been suggested as a promising approach for overcoming resistance to current immune checkpoint therapies. Herein, we report the design, development, and analytical algorithm for comprehensive VISTA-centric tumor immunophenotyping to explore potential tumor biomarkers for novel anti-VISTA therapeutic antibody CI-8993, currently under clinical development in Phase 1 trial. <h3>Methods</h3> Formalin-fixed paraffin embedded (FFPE) tumor tissue sections from 10 cases of non-small cell lung carcinoma (NSCLC) were purchased from NovoVita Histopath Laboratory. Serial tumor tissue sections were double-immunostained with VISTA combined with CD8 (cytotoxic T cell marker), CD4 (T helper cell marker), CD11b (myeloid cell marker), CD68 (monocyte/macrophage marker), CD56 (NK cell marker), CD19 (B cell marker) or Programmed Death-Ligand 1 (PD-L1). <h3>Results</h3> Immunohistochemical analysis revealed the presence of CD8+ cells (9/10 cases), CD4+ cells (3/10 cases), CD11b+ cells (10/10 cases), CD68+ cells (10/10 cases), CD56+ cells (4/10 cases) and CD19+ cells (8/10 cases) in lung tumors. Using double IHC staining, we found that VISTA was expressed in CD8+ cells (5/9 tumors), CD11b+ cells (5/10 tumors) and CD19+ cells (5/8 tumors), whereas VISTA was hardly detectable in CD4+, CD68+ or CD56+ cells. Expression of PD-L1 was detected in cancer cells in 6/10 tumors, whereas VISTA-pos cancer cells were revealed in 1/10 tumors. We developed an algorithm for evaluation of VISTA-centric tumor immunophenotyping and demonstrated that every tumor has a unique cell-type-specific pattern of VISTA expression which could serve as a potential biomarker. <h3>Conclusions</h3> Our results demonstrate that comprehensive VISTA-centric immunophenotyping enables spatially resolved and cell-type-specific characterization of VISTA expression in solid tumors and can serve as applicable bioanalytical approach for identification of potential biomarkers to guide anti-VISTA therapeutic treatment decisions. 

/pdf/20-development-of-vista-centric-tumor-immunophenotyping-as-a-bwxxlook.pdf

20 Development of VISTA-centric tumor immunophenotyping as a novel approach for identification of potential biomarkers for anti-VISTA therapy

https://jhoonline.biomedcentral.com/counter/pdf/10.1186/s13045-022-01321-4

Correction: Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.

https://science.sciencemag.org/content/sci/223/4643/1362.full.pdf

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset

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Effects of cyclosporine in recent-onset juvenile type 1 diabetes: Impact of age and duration of disease

20 Development of VISTA-centric tumor immunophenotyping as a novel approach for identification of potential biomarkers for anti-VISTA therapy

Correction: Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset