Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart.

Immune-checkpoint inhibitors (ICIs) have revolutionized oncology, with nearly 50% of all patients with cancer eligible for treatment with ICIs. However, patients on ICI therapy are at risk for immune-related toxicities that can affect any organ. Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication.

LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice.

Background: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known.

Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis.

Methods: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global knockout mice.

Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis.

Background And Aims: Increasing evidence has shown that immune checkpoint molecules of the T-cell immunoglobulin and mucin domain (Tim) family are associated with diverse physiologic and pathologic processes. Previous studies of the role of Tim-1 in atherosclerosis using anti-Tim-1 antibodies have yielded contradictory results. We thus aimed to investigate atherosclerosis development in Tim-1 deficient mice.

SIRPα - CD47 axis regulates dendritic cell-T cell interactions and TCR activation during T cell priming in spleen.

The SIRPα-CD47 axis plays an important role in T cell recruitment to sites of immune reaction and inflammation but its role in T cell antigen priming is incompletely understood. Employing OTII TCR transgenic mice bred to Cd47-/- (Cd47KO) or SKI mice, a knock-in transgenic animal expressing non-signaling cytoplasmic-truncated SIRPα, we investigated how the SIRPα-CD47 axis contributes to antigen priming. Here we show that adoptive transfer of Cd47KO or SKI Ova-specific CD4+ T cells (OTII) into Cd47KO and SKI recipients, followed by Ova immunization, elicited reduced T cell division and proliferation indices, increased apoptosis, and reduced expansion compared to transfer into WT mice.

A woman presenting with an unusual cause of fulminant liver failure and sepsis.

We present the case of a 61-year-old woman who presented with acutely worsening right upper quadrant pain and was found to be in acute liver failure with Klebsiella pneumoniae bacteremia. Despite aggressive intensive care management, the patient ultimately died of refractory shock attributed to sepsis and fulminant liver failure. On autopsy, she was found unexpectedly to have diffuse intrahepatic cholangiocarcinoma with metastases to regional lymph nodes and intravascular spread to the lungs.

Protective heterologous T cell immunity in COVID-19 induced by the trivalent MMR and Tdap vaccine antigens.

Background: T cells control viral infection, promote vaccine durability, and in coronavirus disease 2019 (COVID-19) associate with mild disease. We investigated whether prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination elicits cross-reactive T cells that mitigate COVID-19.

Methods: Antigen-presenting cells (APC) loaded with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MMR, or Tdap antigens and autologous T cells from COVID-19-convalescent participants, uninfected individuals, and COVID-19 mRNA-vaccinated donors were co-cultured.

FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity.

Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8 T cell-dependent anti-tumor immunity in mice.

Anti-body antibodies in COVID-19.

A new high-throughput screening technique detected autoantibodies in COVID-19 patients specific for many different immunomodulatory extracellular and cell surface proteins, several of which were associated with disease severity and clinical outcomes.

Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal.

Heat shocks T cells down a path to disease.

Febrile temperatures enhance differentiation of CD4 T cells into pathogenic T17 cells that contribute to autoimmune disease.

Increased lymphocyte activation and atherosclerosis in CD47-deficient mice.

CD47, also known as integrin-associated protein (IAP), is a transmembrane protein with multiple biological functions including regulation of efferocytosis and leukocyte trafficking. In this study we investigated the effect of CD47-deficiency on atherosclerosis using a model of adeno-associated virus (AAV)-induced hypercholesterolemia. We observed increased plaque formation in CD47 null mice compared to wild-type controls.

Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

Objective: MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females.

Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities.

Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity.

T cell checkpoint regulators in the heart.

T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance.

CD8-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure.

Heart failure due to pressure overload is frequently associated with inflammation. In addition to inflammatory responses of the innate immune system, autoimmune reactions of the adaptive immune system appear to be triggered in subgroups of patients with heart failure as demonstrated by the presence of autoantibodies against myocardial antigens. Moreover, T cell-deficient and T cell-depleted mice have been reported to be protected from heart failure induced by transverse aortic constriction (TAC) and we have shown recently that CD4-helper T cells with specificity for an antigen in cardiomyocytes accelerate TAC-induced heart failure.

Vasoactive Intestinal Peptide Ameliorates Acute Myocarditis and Atherosclerosis by Regulating Inflammatory and Autoimmune Responses.

Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events.

IL-23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice.

Background: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4 T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice.

Methods And Results: We used heterozygous knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous ( ) mice to investigate the effect of lack of IL-23R in atherosclerosis.

T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure.

We investigated whether CD4-T cells with specificity for an antigen in cardiomyocytes promote the progression from hypertrophy to heart failure in mice with increased pressure load due to transverse aortic constriction (TAC). OT-II mice expressing a transgenic T cell receptor (TCR) with specificity for ovalbumin (OVA) on CD4-T cells and cMy-mOVA mice expressing OVA on cardiomyocytes were crossed. The resulting cMy-mOVA-OT-II mice did not display signs of spontaneous autoimmunity despite the fact that their OVA-specific CD4-T cells were not anergic.

Monocyte-Macrophages and T Cells in Atherosclerosis.

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction.

Unraveling Vascular Inflammation: From Immunology to Imaging.

Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography/computed tomography. Indeed, vascular inflammation is associated with future risk for myocardial infarction and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk.

A role for T helper cells in anti-CTLA-4 therapy.

Comparison of immune responses to CTLA4 and PD-1 blockade uncovers a role for helper T cells in anti-CTLA-4 therapy.

Help not wanted in the joint.

A newly discovered T cell subset that helps B cells is expanded in joints of rheumatoid arthritis patients.

Innate lymphoid cells in atherosclerosis.

The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells.

Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells.

Atherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases.

Defects in CD4+ T cell LFA-1 integrin-dependent adhesion and proliferation protect Cd47-/- mice from EAE.

CD47 is known to play an important role in CD4 T cell homeostasis. We recently reported a reduction in mice deficient in the Cd47 gene (Cd47) CD4 T cell adhesion and transendothelial migration (TEM) in vivo and in vitro as a result of impaired expression of high-affinity forms of LFA-1 and VLA-4 integrins. A prior study concluded that Cd47 mice were resistant to experimental autoimmune encephalomyelitis (EAE) as a result of complete failure in CD4 T cell activation after myelin oligodendrocyte glycoprotein peptide 35-55 aa (MOG) immunization.