Inflammatory bowel diseases (IBD), categorized as Crohn's disease (CD) or ulcerative colitis (UC), are complex disorders of unknown etiology with a spectrum of clinical features which exhibit great variation among affected subjects. The majority of patients, however, will required immunosuppressive and/or immunomodulatory agents which are not universally successful in effective maintaining remission and preventing disease relapse. Recent insights into the basic mechanisms of immune responses and the extension of these concepts to CD and UC have led to the identification of new therapeutic targets which may be more efficacious in IBD therapy by focusing on critical biologic pathways. More recently, it has been suggested that co-stimulatory signals involved in antigen presentation appear to affect immune responses through the up- regulation of an accessory molecule named CD40 ligand (CD40L) on T cells. The interaction between the molecule CD40 and CD40L appears to play a role in CD4 T cell-mediated responses that characterize a variety of autoimmune-mediated disease states including inflammatory bowel disease. Based upon these biologic considerations of CD40-CD40L activity, we believe that human. IBD, both CD and UC, may be diseases which would benefit clinically from therapy directed at the CD40-CD40L pathway. We therefore propose a clinical trial of a humanized anti- CD40L antibody in study subjects with inflammatory bowel disease with the following specific aims: 1) To determine any toxicity and potential benefit from anti-CD40L antibody therapy in patients with steroid-resistant or refractory CD and UC. 2) To determine the incidence of clinical and histologic disease remission in patients with steroid-resistant or refractory CD and UC treated with anti-CD40L antibody therapy. 3) To determine the proportion of patients who remain in sustained clinical remission 12 months after anti-CD40L antibody therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-EWS-I (S1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Ponath, Gerald; Lincoln, Matthew R; Levine-Ritterman, Maya et al. (2018) Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nat Commun 9:5337
Sumida, Tomokazu; Lincoln, Matthew R; Ukeje, Chinonso M et al. (2018) Activated ?-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nat Immunol 19:1391-1402
Nylander, Alyssa N; Ponath, Gerald D; Axisa, Pierre-Paul et al. (2017) Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2:
Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8
Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6
Cao, Yonghao; Nylander, Alyssa; Ramanan, Sriram et al. (2016) CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86:1553-6
Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53
Hernandez, Amanda L; Kitz, Alexandra; Wu, Chuan et al. (2015) Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J Clin Invest 125:4212-22
Marson, Alexander; Housley, William J; Hafler, David A (2015) Genetic basis of autoimmunity. J Clin Invest 125:2234-41
Preusser, Matthias; Lim, Michael; Hafler, David A et al. (2015) Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11:504-14

Showing the most recent 10 out of 41 publications