COVID-19: The Many Ways to Hurt Your Heart

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has become a global pandemic, affecting the lives of billions of individuals [...

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease- and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called “antigen-specific” therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-to-bedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined

The Macrophage in Cardiac Homeostasis and Disease: JACC Macrophage in CVD Series (Part 4).

Macrophages are integral components of cardiac tissue and exert profound effects on the healthy and diseased heart. Paradigm shifting studies using advanced molecular techniques have revealed significant complexity within these macrophage populations that reside in the heart. In this final of a 4-part review series covering the macrophage in cardiovascular disease, the authors review the origins, dynamics, cell surface markers, and respective functions of each cardiac macrophage subset identified to date, including in the specific scenarios of myocarditis and after myocardial infarction. Looking ahead, a deeper understanding of the diverse and often dichotomous functions of cardiac macrophages will be essential for the development of targeted therapies to mitigate injury and orchestrate recovery of the diseased heart. Moreover, as macrophages are critical for cardiac healing, they are an emerging focus for therapeutic strategies aimed at minimizing cardiomyocyte death, ameliorating pathological cardiac remodeling, and for treating heart failure and after myocardial infarction

Turning Human Epidermis Into Pancreatic Endoderm

OBJECTIVE: Human embryonic stem (hES) cells can be differentiated into pancreatic endoderm structures in vitro. The study was performed to determine whether induced pluripotent stem (iPS) cells can be differentiated into similar structures with comparable efficiency. METHODS: We compared the ability of hES cells and iPS cells derived from human epidermal keratinocytes to progressively differentiate into pancreatic endoderm. Human foreskin keratinocytes were reprogrammed to pluripotency by transduction with retroviruses encoding Oct4, Sox2, and Klf4. The resulting keratinocyte-derived iPS (KiPS) cell lines and a hES cell line were subjected to a modified pancreatic endoderm differentiation protocol. Cells and embryoid-body structures derived from both hES and KiPS cells were compared at different stages of development for expression of stem cell and differentiation markers, including Sox2, Oct4, Mixl1, Brachyury, Gsc, FoxA2, Sox17, Hnf4α, Hnf1β, Nkx2.2, Nkx6.1, Hex, Isl1, Pdx1, and Slc2A, via Taqman real-time PCR, flow-cytometry, and/or immunocytochemistry. RESULTS: hES cells and KiPS cells expressed similar levels of the stem cell factors Sox2 and Oct4. Upon differentiation, both cell types underwent remarkably similar changes in gene expression. They acquired the definitive endoderm markers Sox17 and FoxA2. Most Sox17+ and FoxA2+ cells co-expressed Hnf4α and Hnf1β, found in the primitive gut tube, a pancreas precursor. Most FoxA2+ cells were also Pdx1+, and many expressed Nkx2.2, Nkx6.1, and Isl1. CONCLUSIONS: Keratinocyte-derived iPS cells can be differentiated into pancreatic endoderm, and the efficiency of this process is comparable to that seen for hES cells. Thus keratinocytes have the potential to serve as a source of patient-specific pancreatic endoderm for transplantation

Reversal of Autoimmunity by Boosting Memory-like Autoregulatory T Cells

SummaryBlunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8+ T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-γ-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention