Secret Relationship of Regulatory T cells, Tregs, on Basophils

MedicalResearch.com Interview with:
“Basophil” by GreenFlames09 is licensed under CC BY 2.0Jagadeesh BAYRY, DVM, PhD, HDR

Scientist CRCN/Associate Professor-INSERM
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1138
Centre de Recherche des Cordeliers
PARIS , FRANCE

 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Basophils are rare granulocytes that are important for the protection against helminth parasites. In addition, basophils mediate T helper 2 responses, support B cell differentiation, and thus establish a vital link between innate and adaptive immunity. Although rare in number, basophils are implicated in various pathological conditions due to the fact that they undergo rapid activation in response to a wide range of stimuli they receive. These stimuli induce the release of diverse immune mediators including cytokines and mediators of hypersensitivity reactions histamine and leukotriene. Basophils are well known for their pathogenic role in allergic diseases. Recent data also advocate basophils in the pathogenesis of autoimmune and other inflammatory diseases. Therefore, considering the impact of dysregulated functions of basophils on the immune response in various diseases, we deliberated that it is essential to understand the regulatory mechanisms by which basophils are kept in check.

Among immunoregulatory cells, CD4+CD25+FoxP3+ regulatory T cells (Tregs) have been widely studied for their role in immune tolerance and in the maintenance of immune homeostasis. Tregs modulate autoimmune and inflammatory responses by exerting direct suppressive effects on various immune cells including dendritic cells, T cells, macrophages, monocytes, B cells, neutrophils, natural killer cells, and mast cells. In view of emerging reports on the role of basophils in various pathological conditions, we investigated if Tregs are able to control the activation and functions of basophils.

In contrast to the central dogma on Tregs as immunosuppressors, we discovered that human basophils are refractory to Treg-mediated suppression. On the contrary, we found that Tregs stimulate resting basophils to induce the expression of activation markers CD69, CD203c, and CD13, and release cytokines IL-4, IL-8, and IL-13. Treg-induced activation of basophils involves IL-3 and STAT5 but was not contact-dependent. These results provide evidence of direct positive effects that human Tregs have on basophil activation and reveal a previously unrecognized feature of this cell subset well known for immunosuppressive functions.  Continue reading

Inflammatory Cells That Suppress Skin Allergic Reactions Identified

MedicalResearch.com Interview with:
elstarNidhi Malhotra PhD

Boston Children’s Hospital
Division of Allergy and Immunology
Senior Scientist at Elstar Therapeutics Inc.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Allergies such as Atopic Dermatitis (AD) are rampant in the industrialized nations. Why are we more predisposed to developing hypersensitive reactions to innocuous proteins (allergens) is not well understood. To gain better understanding and to develop better therapies, we need to first delve deeper into how our immune system regulates homeostasis in tissues such as skin. The main cell types that thwart inflammatory reactions are known as regulatory T cells. These cells are generated in thymus and reside in secondary lymphoid tissues but they are also prominent at tissue sites such as in dermal layer of skin. In this study, I focused on understanding how Tregs resident in skin are distinct from the Tregs in secondary lymphoid organs such as lymph nodes (LNs). I uncovered that functioning of Tregs in skin is underpinned by a distinct set of genes. One main gene that I found to be highly expressed in skin Tregs but not in LN Tregs is Rora, which encodes for the transcription factor ROR alpha (RORa).

This observation was intriguing as previous studies had elucidated the requirement of RORa in the development of inflammatory type-2 innate lymphoid cells (ILC2s) and it has been considered the antagonizing RORa functioning would curb allergic responses. However, I observed that Tregs require RORa to suppress allergic responses. In particular, RORa regulates the expression of a TNF receptor family member DR3, which binds to the cytokine TL1A. TL1A has a role in enhancing suppressive activity of Tregs while also enhancing type-2 cytokine production from ILC2s. Hence, in the absence of DR3 in Tregs, we believe more TL1A is available to ILC2s resulting in unrestrained allergic responses.  Continue reading

New Technique Allows Mining of Specific Antibodies From B Cells

MedicalResearch.com Interview with:

Dr. Sarav Rajan, PhD Scientist Antibody Discovery and Protein Engineering MedImmune

Dr. Rajan

Dr. Sarav Rajan, PhD Scientist
Antibody Discovery and Protein Engineering
MedImmune

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: During an infection, B cells (a type of white blood cell) create antibodies against antigens present on a pathogen. These cells can be extremely rare, and finding them among the millions of other cells is extremely challenging.

Existing methods to examine B cells require a trade-off: either capture the full sequence repertoire by next-generation sequencing but functionally screen just a subset, or culture a subset of B cells and fully screen them. Instead, our method captures the complete repertoire within a typical blood draw and screens all its members to identify the rare antigen-positive antibodies. Using a new microfluidic approach, we recovered the antibody genes from one million B cells encapsulated in picoliter-scale droplets, breaking through a widely-published view that amplifying from single cells in such small volumes is inefficient. The resulting library seamlessly integrates into our high-throughput screening infrastructure to enable rapid isolation of desired antibodies. Using this method, we were able to isolate a panel of rare cross-reactive antibodies targeting influenza.

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Statins Reduce Inflammation As Well As LDL

MedicalResearch.com Interview with:

Dr. Johan Frostegård MD PhD Professor of medicine Karolinska Institutet's Institute of Environmental Medicine and Consultant at Karolinska University Hospital's Emergency Clinic.

Dr. Johan Frostegård

Dr. Johan Frostegård MD PhD
Professor of medicine
Karolinska Institutet’s Institute of Environmental Medicine and
Consultant at Karolinska University Hospital’s Emergency Clinic

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Statins are one of the worlds most sold medications, which has generated large profits, but also, in my opinion, helped many people. Still, side effects are much discussed after more than 2 decades of use, as exemplified by a current debate between Lancet and BMJ (the former has the opinion that side effects are not major issues, but the latter do not agree). Also the exact role of LDL (low density lipoprotein, also known as the ”bad cholesterol”) as a risk factor is discussed, and can vary, according to many researchers. LDL levels are important among middle aged persons, especially men, as a risk markers for cardiovascular disease, especially myocardial infarction. LDL is most likely less important as a risk factor in individuals above 60 years of age, and also among women – as compared to middle aged men.

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Early Immune Intervention May Prevent Atopic March of Eczema and Allergies

MedicalResearch.com Interview with:
Emma Guttman-Yassky, MD, PhD

Professor of Dermatology and Immunology
Vice Chair of the Department of Dermatology at the Icahn School of Medicine and
Amy S. Paller, MD
Walter J. Hamlin Professor
Chair of the Department of Dermatology at Northwestern

MedicalResearch.com: What is the background for this study?

Response: Researchers for the first time have identified the skin phenotype of pediatric eczema or atopic dermatitis (AD) in infants, opening the door for personalized treatment approaches for young children with eczema. The study, led by researchers at the Icahn School of Medicine at Mount Sinai and Northwestern University’s Feinberg School of Medicine, was published online today in the Journal of Allergy and Clinical Immunology.

Emma Guttman-Yassky, MD, PhD, Professor of Dermatology and Immunology, and Vice Chair of the Department of Dermatology at the Icahn School of Medicine, and Amy S. Paller, MD, Walter J. Hamlin Professor and Chair of the Department of Dermatology at Northwestern, investigated lesional and non-lesional skin biopsies from 19 AD infants under the age of five, and compared them to age-matched pediatric controls, in addition to adult AD biopsies. The researchers found that the non-lesional, or normal-appearing, skin of young children with early eczema is already highly abnormal with significant immune activation, simulating that of lesional skin of adults with many years of active disease.

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Immune Markers Of Wheat Sensitivity In Patients Without Celiac Disease Identified

MedicalResearch.com Interview with:

Armin Alaedini, PhD Assistant Professor Department of Medicine & Institute of Human Nutrition Columbia University Medical Center New York, NY 10032

Dr. Armin Alaedini

Armin Alaedini, PhD
Assistant Professor
Department of Medicine & Institute of Human Nutrition
Columbia University Medical Center
New York, NY 10032

MedicalResearch.com: What is the background for this study?

Response: It has been a mystery why some people experience a range of symptoms in response to the ingestion of wheat and related cereals, even though they do not have celiac disease (an autoimmune disorder) or wheat allergy. Both gastrointestinal (GI) symptoms, most commonly abdominal pain, diarrhea, and bloating, as well as extra-intestinal symptoms, such as fatigue, anxiety, depressed mood, and cognitive difficulties are reported by patients. The identity of the component(s) of wheat responsible for triggering the symptoms remains uncertain and it is not clear if gluten or non-gluten molecules are involved. There is evidence to indicate that wheat sensitivity also affects a subset of patients with irritable bowel syndrome (IBS), a common disorder. Despite the interest from the medical community and the general public, the causes and mechanism of the associated symptoms have remained unknown and no biomarkers are available to aid in the diagnosis of patients.

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Promising Biologic Stimulates Blood Flow Into Critical Limb Ischemia

MedicalResearch.com Interview with:

Dr. Emerson C. Perin MD, PhD Texas Heart Institute Medical Director, BSLMC Catheterization Laboratory Director, Research in Cardiovascular Medicine Medical Director, Stem Cell Center

Dr. Emerson Perin

Dr. Emerson C. Perin MD, PhD
Texas Heart Institute
Medical Director, BSLMC Catheterization Laboratory
Director, Research in Cardiovascular Medicine
Medical Director, Stem Cell Center 

MedicalResearch.com: What is the background for this study?

Dr. Perin: Critical limb ischemia (CLI) is a devastating and debilitating disease characterized by reduced blood flow to the legs, frequently as a consequence of atherosclerosis. Patients with CLI have a poor prognosis and live with chronic pain and disability. The disease manifests clinically as pain during rest and compromised wound healing, often resulting in ulcers that don’t heal, which can lead to amputation. Moreover, Critical limb ischemia is a deadly disease, with an annual mortality rate of about 20%. The only effective treatment option is revascularization, but not all CLI patients are good candidates for this approach, and even for those who are, procedures can fail. These patients face a dismal prospect as no other effective treatment options are available. Clearly, new therapeutic strategies are desperately needed for this group of patients.

One of the most exciting new approaches for Critical limb ischemia patients who have no options is the concept of therapeutic angiogenesis—improving regional blood flow by facilitating the growth of blood vessels. This can be accomplished by delivering angiogenic factors to the area in need of improved blood supply. Hepatocyte growth factor (HGF) is a promising novel biologic for use in this way because it’s a powerful angiogenic agent that stimulates cell proliferation and migration. Delivering HGF into the ischemic limbs of patients with CLI may result in beneficial effects that help restore compromised blood flow to the area and encourage better healing of wounds. VM202 is a plasmid DNA that simultaneously expresses two isoforms of HGF, mimicking the way the body produces HGF. On the basis of favorable results from phase 1 clinical trials showing that gene therapy with VM202 was safe, well-tolerated, and potentially beneficial in patients with ischemic diseases, we conducted a phase 2, dose-escalation clinical trial in patients with Critical limb ischemia.

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