https://caltcm.memberclicks.net/assets/documents/acc_aha_chf_2013_guidelines.pdf

2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

/pdf/the-blockade-of-immune-checkpoints-in-cancer-immunotherapy-j2cp4ba5s9.pdf

The blockade of immune checkpoints in cancer immunotherapy

BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

/pdf/pd-1-blockade-in-tumors-with-mismatch-repair-deficiency-1eb0ztv7j7.pdf

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.

/pdf/pd-1-and-pd-l1-immune-checkpoint-blockade-to-treat-breast-2u575m0pog.pdf

PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Dilated cardiomyopathy is a severe pathology of the heart with poorly understood etiology. Disruption of the gene encoding the negative immunoregulatory receptor PD-1 in BALB/c mice, but not in BALB/c RAG-2-/- mice, caused dilated cardiomyopathy with severely impaired contraction and sudden death by congestive heart failure. Affected hearts showed diffuse deposition of immunoglobulin G (IgG) on the surface of cardiomyocytes. All of the affected PD-1-/- mice exhibited high-titer circulating IgG autoantibodies reactive to a 33-kilodalton protein expressed specifically on the surface of cardiomyocytes. These results indicate that PD-1 may be an important factor contributing to the prevention of autoimmune diseases.

http://science.sciencemag.org/content/sci/291/5502/319.full.pdf

Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice

Background Familial hypertrophic cardiomyopathy can be caused by mutations in the genes for β cardiac myosin heavy chain, α-tropomyosin, or cardiac troponin T. It is not known how often the disease is caused by mutations in the tropomyosin and troponin genes, and the associated clinical phenotypes have not been carefully studied. Methods Linkage between polymorphisms of the α-tropomyosin gene or the cardiac troponin T gene and hypertrophic cardiomyopathy was assessed in 27 families. In addition, 100 probands were screened for mutations in the α-tropomyosin gene, and 26 were screened for mutations in the cardiac troponin T gene. Life expectancy, the incidence of sudden death, and the extent of left ventricular hypertrophy were compared in patients with different mutations. Results Genetic analyses identified only one α-tropomyosin mutation, identical to one previously described. Five novel mutations in cardiac troponin were identified, as well as a further example of a previously described mutation. The cl...

https://www.nejm.org/doi/pdf/10.1056/NEJM199504203321603

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.

Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice

OBJECTIVES--To elucidate the potential role of cytokines in the pathogenesis of cardiomyopathy and myocarditis BACKGROUND--Experimental studies show that certain cytokines depress myocardial contractility and that tumour necrosis factor-alpha plays an important part in the pathogenesis of myocardial injury in animal models of viral and autoimmune myocarditis METHODS--Plasma interleukin 1-alpha, interleukin 1-beta, interleukin-2, interleukin-6, tumour necrosis factor-alpha, tumour necrosis factor-beta, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor, interferon-alpha and interferon-gamma were measured in 13 patients with acute myocarditis, 23 patients with dilated cardiomyopathy, 51 patients with hypertrophic cardiomyopathy, nine patients with acute myocardial infarction, 18 patients with angina pectoris, 12 patients with essential hypertension and 17 healthy controls RESULTS--Increased concentrations of cytokines were not detected in the controls In patients with acute myocarditis, interleukin 1-alpha was detected in 23% (mean (SD) 25 (11) pg/ml), tumour necrosis factor-alpha in 46% (61 (31) pg/ml), and macrophage colony stimulating factor was 25 (18) ng/ml (normal 19 (04)) In patients with dilated cardiomyopathy, tumour necrosis factor-alpha was detected in 35% (402 (555) pg/ml) In patients with hypertrophic cardiomyopathy, interleukin-2 was detectable in 14% (2318 (4738) pg/ml) and tumour necrosis factor-alpha ws detected in 20% (992 (1517) pg/ml) The concentration of macrophage colony stimulating factor was raised in patients with acute myocardial infarction Granulocyte colony stimulating factor was often increased in myocarditis, cardiomyopathies, acute myocardial infarction, and angina pectoris--suggesting activation of macrophages and/or endothelial cells--but this increase was not specific to these diseases Increased concentrations of cytokines were not found in patients with essential hypertension CONCLUSION--These results suggest that cytokines may play a part in the pathogenesis of myocardial injury in myocarditis and cardiomyopathies and that further studies to explore the potential pathogenetic role of cytokines in myocardial diseases may be warranted

https://heart.bmj.com/content/heartjnl/72/6/561.full.pdf

Increased circulating cytokines in patients with myocarditis and cardiomyopathy.

Objectives-To elucidate thepotential roleofcytokines inthepathogenesis of cardiomyopathy andmyocarditis. Background-Experimental studies show thatcertain cytokines depress myocardial

Akira Matsumori

Papers

Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice

Increased circulating cytokines in patients with myocarditis and cardiomyopathy.

Increased circulating cytokines inpatients with myocarditis andcardiomyopathy