Dynamic duo: combination therapy reverses type 1 diabetes
Researchers have now carefully crafted a combination therapy that reverses recent-onset type 1 diabetes in 2 animal models of disease. By combining an oral with an intranasal therapy for type 1 diabetes that have individually shown beneficial, but limited, effects in previous studies, Matthias von Herrath and colleagues at the La Jolla Institute for Allergy and Immunology deliver a one-two punch, and prove that, in this case, 2 treatments work together better than one. The study appears online on April 20 in advance of print publication in the May issue of the Journal of Clinical Investigation.
In patients with type 1 diabetes, the autoimmune response destroys insulin-producing cells (beta cells) in pancreatic islets, thereby subjecting these individuals – often children or young adults – to a lifetime of insulin injections. To prevent disease, autoreactive immune cells need to be suppressed or eliminated without negative side-effects. One treatment strategy that has been shown to suppress beta cell killing is the delivery of an antibody against the CD3 molecule expressed on most T cells. This antibody promotes the function of regulatory T cells (Tregs), which put the brakes on an overaggressive immune response. However, chronic "body-wide" suppression of the immune system in this way puts patients at risk for malignancies or reactivation of dormant viral infections, consequently dampening enthusiasm for this monotherapeutic approach.
One of the critical questions that has remained is how do we prevent immune responses against only insulin-producing cells? Promising data in animal models has shown that it is possible to deliver beneficial immune modulatory molecules to the pancreatic islets by inducing islet antigen–specific Tregs. However, this intervention only appears effective early in the pre-diabetic stage.
In their JCI study, von Herrath and colleagues show that combination treatment with a low-dose, orally-delivered CD3epsilon-specific antibody as well as an intranasally-delivered proinsulin peptide synergizes to reverse recent-onset type 1 diabetes in mice, with much greater efficacy than monotherapy with anti-CD3 or peptide alone. As the induced Tregs acted to specifically shield islets from autoimmune destruction, and only a low dose of anti-CD3 antibody was required, this strategy is also expected to reduce the potential for adverse side effects resulting from the immune suppression. Suppression of the immune response in this way promotes pancreatic beta cell regeneration through the natural regenerative process. If similar success is observed in humans, this dynamic therapeutic duo may hold great potential for the treatment of individuals with recent-onset type 1 diabetes.
TITLE: Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs.
AUTHOR CONTACT:
Matthias von Herath
La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
Phone: (858) 558-3671; Fax: (858) 558-3579; E-mail: matthias@liai.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27191
DERMATOLOGY
Show me some skin: Failed wound healing promotes psoriasis
Inflammatory skin disorders result in many changes to the skin surface, one of which is an impairment of the epidermal barrier that protects the body from an often hostile environment. Now, in a study appearing online on April 20 in advance of print publication in the May issue of the Journal of Clinical Investigation, Julia Segre and colleagues from the National Human Genome Research Institute in Bethesda, Maryland report that the converse is also true: that damage to the skin surface actually promotes development of the chronic inflammatory condition psoriasis, and that the protein connexin 26 is involved in this process.
The authors examined newborn, juvenile, and adult mice lacking the protein Klf4, which have a severe defect in epidermal barrier formation. They found that connexin 26 (Cx26) – a protein that helps form channels between neighboring cells for the distribution of nutrients and signaling molecules – was overexpressed in these mice. Persistent Cx26 expression kept wounded skin in a state of hyper-proliferation, which prevented wound healing and triggered an ongoing inflammatory reaction. The authors concluded that Cx26 expression must be downregulated in utero in order for the epidermal barrier to form before birth, and similarly downregulated after wound healing to allow the skin to repair itself. The study suggests that the most effective treatments for inflammatory skin disorders might be those that suppress the immune response and enhance the maturation of new skins cells in order to restore the skin surface to normal after injury.
TITLE: Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response
AUTHOR CONTACT:
Julia A. Segre
National Human Genome Research Institute, Bethesda, Maryland, USA.
Phone: (301) 402-2314; Fax: (301) 402-4929; E-mail: jsegre@nhgri.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27186
AUTOIMMUNITY
AIRE determines target of the autoimmune response in type 1 diabetes
The factors that direct the autoimmune response to target a specific organ or organs are poorly understood. In type 1 diabetes it is the beta cells within pancreatic islets that are specifically under autoimmune attack, although the exact molecule(s) recognized by the autoreactive T cells is still being debated. In a study appearing online on April 20 in advance of print publication in the May issue of the Journal of Clinical Investigation, Mitsura Matsumoto and colleagues from the University of Tokushima, Japan, examined mice with type 1 diabetes in which the autoimmune regulator (AIRE) was lacking. The authors found that in the absence of AIRE, the target cells primarily attacked by the autoreactive T cells were no longer islet beta cells, but acinar cells in the mouse pancreas. This change in specificity was associated with production of an autoantibody against an antigen expressed predominantly by acinar cells. Consistent with this change, the animals were resistant to the development of diabetes. The study suggests a novel role for AIRE in the pathogenesis of autoimmune disease, one in which AIRE strongly modifies the specificity of the autoreactive T cells of the immune response within and for particular organs.
TITLE: Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
AUTHOR CONTACT:
Mitsura Matsumoto
University of Tokushima, Tokushima, Japan.
Phone: 81-88-633-7432; Fax: 81-88-633-7434; E-mail: mitsua@ier.tokushima-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=26971
PHYSIOLOGY
Cooperation killed the kidney: pairs of genes interact in renal disease
Within the kidney, thousands of structures known as glomeruli filter harmful or unnecessary substances out of blood and into the urine. During the condition known as focal segmental glomerulosclerosis (FSGS), scar tissue forms in segments of some of the glomeruli. This results in the persistent release of protein from the urine and progression to renal failure. Despite a growing understanding of the genes involved in FSGS, a clear genetic diagnosis cannot be made in the vast majority of patients. In a study appearing online on April 20 in advance of print publication in the May issue of the Journal of Clinical Investigation, Andrey Shaw and colleagues from Washington University, St. Louis, Missouri tested whether combinations of genetic heterozygosity of genes that alone do not result in clinical kidney disease could function together to cause FSGS.
The authors crossed mice heterozygous for the gene Cd2ap with mice heterozygous for the kidney-relevant genes Fyn, Synpo or Neph1. They found that animals with bigenic heterozygosity for Cd2ap with Fyn or Synpo, but not Neph 1, had increased protein release in their urine and clinical changes within their kidney consistent with FSGS. This suggests that combined mutations of genes that encode the proteins Cd2ap, Fyn or Synpo may account for disease in some patients with FSGS.
TITLE: A bigenic mouse model of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin
AUTHOR CONTACT:
Andrey S. Shaw
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: (314) 362-4614; Fax: (314) 747-4888; E-mail: shaw@pathbox.wustl.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27400
IMMUNOLOGY
IL-4 expression by mast cells modifies the immune response in multiple sclerosis
IL-4 is expressed by many types of immune cells and it can act on a variety of other immune as well as non-immune cells to modulate the immune response. This broad range of effects necessitates strict control of IL-4 expression as inappropriate IL-4 expression is associated with allergic disease, autoimmunity, and an inability to clear some infections.
In a study appearing online on April 20 in advance of print publication in the May issue of the Journal of Clinical Investigation, Melissa Brown and colleagues demonstrate that IL-4 expression by mast cells is regulated by proteins known as Ikaros and GATA, and this expression contributes to the development of a multiple sclerosis–like autoimmune disease in mice. Interestingly, the authors found that IL-4 expression by mast cells differed in different strains of mice. In sum, the study further points to the role of the mast cell in sophisticated gene regulation relevant to the immune response.
TITLE: Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenc Th1 responses in EAE
AUTHOR CONTACT: Melissa A. Brown Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Phone: (312) 503-0108; Fax: (312) 503-4839; E-mail: m-brown12@northwestern.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27227
Journal
Journal of Clinical Investigation