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An article published last week in Disease Models and Mechanisms by Dawn Smilek, MD, PhD, Mario Ehlers, MD, PhD, and Jerry Nepom, MD, PhD, provides a review of mechanisms involved in the disruption of tolerance to self-antigens in autoimmune disease, highlighting where those mechanisms can be targeted as a means of restoring tolerance and durably reversing autoimmune pathology. Given the complexity of pathways that contribute to autoimmune disease, effective and long-lasting treatment will likely require rational combinations of therapeutics that enhance regulatory components of the immune system, while diminishing antigen-specific effectors and the innate immune response. This approach is consistent with the ITN’s recently-launched PAUSE study in psoriasis, which will assess the combination of ustekinumab (anti-IL12/23) to first reduce T effector cells in the skin, followed by abatacept (CTLA-4 Ig) to prevent pathogenic re-activation of repopulating cells by means of co-stimulatory blockade. Other ITN trials in development will similarly use mechanistically-driven combination therapy approaches to tolerance.

Today the ITN launched the PAUSE study (ITN059AI, “Efficacy of Ustekinumab followed by Abatacept for the Treatment of Psoriasis Vulgaris”), which will test the combination of two biologics, ustekinumab (Janssen Biotech, Inc.) and abatacept (Bristol-Myers Squibb), in psoriasis patients. This study is being led by James Krueger, MD, PhD (The Rockefeller University). PAUSE will test whether the sequential combination of anti-IL12/23 (ustekinumab) and CTLA-4 Ig (abatacept) in psoriasis will produce changes in the immune system that will lead to durable disease remission.

Creating durable disease remission in type 1 diabetes has proved challenging: etiology remains uncertain and immune interventions have only been able to delay disease progression temporarily. To better understand underlying disease pathways, the ITN conducts sophisticated mechanistic assays on high-quality specimens collected from each of its clinical trials. After a study is complete, unused mechanistic specimens are available to the scientific community for further research through the ITN’s Clinical Trials Research Portal, TrialShare.

The promise of autologous stem cell transplantation in patients with autoimmune disease is that the newly reconstituted immune system will be reset in a way that no longer favors autoimmunity. The ITN’s HALT-MS study (High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis) used high-dose immunosuppression followed by an autologous stem cell transplant in 24 relapsing, remitting multiple sclerosis (MS) patients in an attempt to reconstitute a healthy immune system. To better understand the post-HSC transplanted immune system, ITN investigators used a high-throughput, deep-sequencing technology (Adaptive Biotechnologies, ImmunoSEQTM Platform) to compare the T cell repertoire at baseline, 2 months post-transplant, and 12 months post-transplant. This is one of the first studies to quantitatively compare the baseline T cell repertoire with the reconstituted repertoire following autologous stem-cell transplant, and has provided a heretofore unseen in-depth analysis of how the immune system reconstitutes itself following lympho-ablative therapy. The results are published today online in the Journal of Clinical Investigation.

The National Institute of Allergy and Infectious Disease (NIAID/NIH) announced that the Immune Tolerance Network (ITN) has been awarded a UM1 grant for a Collaborative Network for Clinical Research on Immune Tolerance (RFA-AI-12-043). This award represents the third NIH funding disbursement since the ITN’s inception in 2000. The current grant, covering the next seven years, will allow the ITN to continue to develop, fund and implement mechanistically-focused clinical trials for novel therapies in transplantation, allergy and autoimmune diseases.

The ITN’s ACCEPTOR study (Post-transplant Cyclophosphamide) in kidney transplant is now open for enrollment at Johns Hopkins University.  The ACCEPTOR study, led by Lode Swinnen, MD, Ephraim Fuchs, MD, and Robert Montgomery, MD (Johns Hopkins Hospital) will combine hematopoietic stem cell (HSC) and kidney transplants as a means to potentially promote tolerance to the donor kidney.  

The ITN’s AVATARS study in ANCA-associated Vasculitis (AAV) opened for enrollment today at the University College London. The AVATARS study (Defining Immune Tolerance in ANCA-associated Vasculitis) led by Alan Salama, MD, PhD (University College London) and Peter Merkel, MD (University of Pennsylvania) is a non-interventional, prospective study that will collect blood specimens from patients with AAV with the goal of identifying biomarkers of tolerance.

The International Diabetes Federation (IDF) annual meeting (December 2-6, 2013) and Immunology of Diabetes Society (IDS) annual meeting (December 7-11, 2013) in Australia will feature multiple talks on recent findings from the Immune Tolerance Network's ( ITN’s) portfolio of type 1 diabetes studies. Type 1 diabetes is a challenging disease where so far no therapeutic has been able to reverse or permanently halt the autoimmune attack on pancreatic β-cells. Clinical trials with immune modulating agents have had only modest clinical effects, but mechanistic data from these studies is contributing to the growing body of evidence about how cellular changes may relate to clinical outcomes, providing insights into how future treatments should be tailored.

Clinical data from the ITN’s ACCESS study (Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis) will be presented at two upcoming conferences. The ACCESS study examined whether the combination of abatacept (CTLA4-Ig) and cyclophosphamide is able to better induce tolerance compared to the Euro-Lupus regimen (low-dose pulse cyclophosphamide).

The Immune Tolerance Network (ITN) is retiring ITN BioShare. ITN’s inventory of clinical trial biospecimens is now available through ITN TrialShare. Now that ITN’s biorepository is accessible through TrialShare, all web traffic to BioShare will redirect to www.ITNTrialShare.org.