Tag: autoimmune disease

Study explores emerging role of NAD+ in innate and adaptive immune responses

In a pre-clinical model, researchers find that NAD+ can trigger a response that protects against lethal infections

BRIGHAM AND WOMEN’S HOSPITAL

Researchers at Brigham and Women’s Hospital (BWH) have discovered a new cellular and molecular pathway that regulates CD4+ T cell response–a finding that may lead to new ways to treat diseases that result from alterations in these cells. Their discovery, published online in the Journal of Allergy and Clinical Immunology, shows that administering nicotinamide adenine dinucleotide (NAD+), a natural molecule found in all living cells, shuts off the capacity of dendritic cells and macrophages to dictate CD4+ T fate. Researchers found that NAD+ administration regulated CD4+ T cells via mast cells (MCs), cells that have been mainly described in the context of allergy, exclusively.

“This is a novel cellular and molecular pathway that is distinct from the two major pathways that were previously known. Since it is distinct and since it has the ability to regulate the immune system systemically, we can use it as an alternative to bypass the current pathways,” said Abdallah ElKhal, PhD, BWH Department of Surgery, senior study author.

CD4+ T helper cells and dendritic cells play a central role in immunity. Alterations or aberrant dendritic cells and T cell responses can lead to many health conditions including autoimmune diseases, infections, allergy, primary immunodeficiencies and cancer.

As of today, two major pathways have been described to regulate CD4+ T cell response. The first pathway was described by Peter C. Doherty and Rolf M. Zinkernagel (1996 Nobel prize winners) showing the requirement of MHC-TCR signaling machinery. More recently, a second mechanism involving the Pathogen or Damage Associated Molecular Patterns (PAMPs or DAMPs) was unraveled by Bruce A. Beutler and Jules A. Hoffmann (2011 Nobel Prize winners). Of importance, both pathways require antigen presenting cells (APCs) in particular dendritic cells (DCs) or macrophages (Mφ). Elkhal’s novel pathway is distinct from the two previous ones and may offer a path forward for novel therapeutic approaches.

For the current study, BWH researchers performed pre-clinical trials using an experimental infection model. They showed that mast cell-mediated CD4+ T cell response protects against lethal doses of infection (Listeria monocytogenes). Mice treated with NAD+ had a dramatically increased survival rate when compared to the non-treated group.

“Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity via MCs, exclusively, and underscores the therapeutic potential of NAD+ in the context of a myriad of diseases including autoimmune diseases, hemophilia, primary immunodeficiencies and antimicrobial resistance,” said Elkhal.

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This work was supported by the National Institutes of Health R01NS073635 and R01MH110438, R01 HL096795 and U01 HL126497, R01AG039449. Co-authors were supported by the Swiss Society of Cardiac Surgery, FIS-ISCIII (grant PI10/02 511) and Fundación Ramón Areces (CIVP16A1843).

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Source: https://www.eurekalert.org/pub_releases/2018-02/bawh-see022318.php

New Discovery in Regulating Autoimmune Diseases

A natural molecule delays disease onset and reverses disease progression

By MARJORIE MONTEMAYOR-QUELLENBERG | October 14, 2014

The main function of the immune system is to protect against diseases and infections. For unknown reasons our immune system attacks healthy cells, tissues and organs in a process called autoimmunity, which can result in diseases such as multiple sclerosis, Type 1 diabetes, lupus or rheumatoid arthritis. There are currently no existing cures for these diseases.

Now, in a new study by researchers at Brigham and Women’s Hospital, a potential treatment may be on the horizon. Researchers found that NAD+, a natural molecule found in living cells, plants and food, protects against autoimmune diseases by altering the immune response and turning “destructive” cells into “protective” cells. The molecule is also able to reverse disease progression by restoring damaged tissue caused by the autoimmunity process.

“Our study is the first to show that NAD+ can tune the immune response and restore tissue integrity by activating stem cells,” said Abdallah ElKhal, HMS instructor in surgery at Brigham and Women’s Division of Transplant Surgery and Transplantation Surgery Research Laboratory and senior study author. “These findings are very novel and may serve for the development of novel therapeutics.”

The scientists performed preclinical trials using experimental autoimmune encephalomyelitis, a preclinical model for human multiple sclerosis. They showed that NAD+ can block acute or chronic inflammation by regulating how immune cells, called CD4+ T cells, differentiate. Mice receiving CD4+ T cells along with NAD+ present had a significant delayed onset of disease, as well as a less severe form, therefore demonstrating the molecule’s protective properties.

“This is a universal molecule that can potentially treat not only autoimmune diseases but other acute or chronic conditions such as allergy, chronic obstructive pulmonary disease, sepsis and immunodeficiency,” said Stefan G. Tullius, HMS professor of surgery, Brigham and Women’s Hospital’s chief of Transplant Surgery, director of Transplantation Surgery Research and lead study author.

Moreover, the researchers demonstrated that NAD+ can restore tissue integrity which may benefit patients that have advanced tissue damage caused by autoimmune diseases. In terms of next steps, ElKhal notes that the lab is currently testing additional pathways and the clinical potential of NAD+.

“Since this is a natural molecule found in all living cells, including our body, we hope that it will be well-tolerated by patients,” said ElKhal. “Thus, we hope that its potential as a powerful therapeutic agent for the treatment of autoimmune diseases will facilitate its use in future clinical trials.”

The Transplant Surgery Research Laboratory and Dr. ElKhal’s work is supported by the National Institutes of Health and the Carlos Slim Foundation.

Source: https://hms.harvard.edu/news/new-discovery-regulating-autoimmune-diseases?fbclid=IwAR0BAmidqYaaBP-7Qm7Ob7SBmqO0e_FdFRJNS_uWF7pnxYYNuWJPDew6Pio


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