Clinical Studies of Inflammatory Bowel Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In the past year the Mucosal Immunity Section has been engaged in a number of on-going research studies involving patients with inflammatory bowel disease (IBD), common variable immunodeficiency and X-linked agammaglobulinemia. In the area of IBD, we are conducting studies of IBD risk polymorphisms involving the LRRK2 gene region with the ultimate goal of exploring the capacity of LRRK2 kinase inhibitors to serve as a treatment modality in Crohn's disease. On this basis we are collaborating with Dr. Inga Peter and her colleagues at the Icahn Mt. Sinai Medical Center in New York who are developing LRRK2 kinase inhibitors with increased capacity to localize in the gastrointestinal tract. Dr. Peter and her colleagues also have access to a large IBD patient population that has made available to us for study. Recently, it has been shown that LRRK kinase is active in the phosphorylation of NLRC4 and thus is a potential activator of the NLRC4 inflammasome. During this period we have studied the capacity of DCs generated from peripheral blood of Crohn's disease sent to us by our collaborators at Icahn Mt. Sinai Medical Center to respond to NLRC4 stimulation in the absence and presence of a LRRK2 kinase inhibitor (termed C-82). We found that patient DCs produce significantly greater amounts of IL-1beta and IL-18 as a result of NlRC4 stimulation than control individuals. In addition, patient DC IL-1beta production declines in the presence of LRRK2 inhibitor whereas control DC does not. Finally, neither patient nor control DC IL-18 production decreases in the presence of inhibitor. These studies strongly suggest that LRRK2 kinase inhibition has an down-regulatory effect on NLRC4 inflammasome-induced IL-1beta production but not IL-18 production and therefore has a preferential effect on the more pro-inflammatory aspect of NLRC4-induced inflammation. In this period, we continued our on-going studies of the safety and and immunologic effects of the administration of vorinostat, a histone deacetylase (HDAC) inhibitor. The Clinical Protocol guiding the execution of this study (Protocol # 17-I-0101) has obtained NIAID IRB and FDA approval. The target patients are those individuals who have failed other forms of Crohn's disease therapy and who are nevertheless suitably prepared for treatment. Our main investigative goal, besides evaluation of vorinistate safety is to evaluate the immunologic effects of HDAC inhibitor therapy including effects on regulatory T cells. To date, we have enrolled and treated two Crohns disease patient disease, each with sufficient inflammation and narrowing of the ileocecal area of the small bowel. Both patients had previously received medical regimens consisting of steroids, immunomodulators and/or biologics (including anti-TNF-a)without gaining control of disease. After 12 weeks of vorinostat therapy both patient had significant improvement in abdominal pain, cramping as well as improvement in diarrheal symptoms. In addition, vorinostat administration resulted in decreased CDAI levels (Crohns disease activity index score). These results hint that vorinostat may be a new avenue of treatment for IBD patients but additional patient studies are required to verify this possibility. In the area of CVID we have continued to focus on the gastrointestinal manifestations of this heterogeneous disease, i.e., patients with a CVID-entropathy characterized by diarrhea, malabsorption and villous atrophy. In prior studies of CVID we established that the CVID enteropathy is driven by cells producing IFN-gamma and little or no IL-17. In addition, we collaborated with Drs. Andriy Morgan and Natalia Stulzhenko of Oregon State University in studies that led to the finding that CVID patients with enteropathy exceedingly reduced levels of IgA in intestinal biopsies whereas those patients without enteropathy have more moderate reduction in levels of IgA. This finding indicates that enteropathy occurs in the subset of CVID patients with severe mucosal B cell immunodeficiency affecting the mucosal immunoglobulin, IgA. Given the fact that a Th1 (IL-12-driven) process is a major contributor to CVID enteropathy, it was reasonable to assume that IL-12 blockade by anti-IL-12p40 (ustekinumab) administration would lead to a decrease in gut inflammation and improvement of gastrointestinal symptoms. In an initial single dose study testing this possibility CVID enteropathy patients (n=3) received a single induction dose (270 mg 3.9 mg/kg for a typical 70 kg patient) of ustekinumab. All patients demonstrated significant improvement in stool pattern with a change from watery consistency to that of soft-formed consistency. All 3 patients have completed 6 months of follow-up study with two patients having an observed clinical response lasting for approximately 4-5 months duration. However, each of these patients have had a subsequent relapse of symptoms (diarrhea, weight loss and abdominal bloating complaints) within 6 months of their last dose. In the light of these results, we initiated a new, multi-dose study, wherein CVID enteropathy patients received an induction dose of 270 mg ustekinumab followed by a maintenance dose of 90 mg ustekinumab every 8 weeks through the week 40 study point. Patients included in this new study included three individuals previously treated on the single dose study (who met re-enrollment eligibility criteria) as well as an additional four patients who had not participated in the single dose study. After at least 20 weeks on this regimen all of the patients have exhibited clinical improvement marked by decreased bowel movement frequency, improved stool consistency, and decreased abdominal pain or bloating. This was accompanied by normalization of serum albumin and total protein levels as well as inflammatory markers such as fecal calprotectin. Most notably, patients exhibited weight gain ranging from 5 to 50 kg. Sample studies and data analysis has now been completed. All remaining coded research samples will be stored for future use on the 89-I-0158, natural history study of humoral immunodeficiencies. In the previous Annual Report we discussed extensive studies (now published) showing that Bruton Tyrosine Kinase (BTK) negatively regulates the NLRP3 inflammasome. As a consequence, mice with genetically-determined BTK dysfunction exhibited enhanced DSS-colitis due to increased lamina propria IL-1beta production that is responsive to agents that inhibit IL-1beta signaling. This correlated with the fact that Crohn's disease occurs with increased frequency in patients with BTK deficiency (patients with X-linked agammaglobulinemia). On the basis of these findings we initiated a study of treatment of Crohn's disease occurring in patients with X-linked agammaglobulinemia to determine if this form of Crohn's disease is uniquely susceptible to treatment with a IL-1beta signaling inhibitor (anakinra). So far, three XLA patients have been evaluated by peripheral blood analysis and via mRNA scope analysis of intestinal biopsy material. Two patients were found to have increased IL-1 beta secretion from peripheral and concomitant analysis of intestinal tissue revealed an increase in IL-18 expression. These patients were placed on Anakinra to block effects of IL-1 beta activation in conjunction with Ustekinumab (anti-IL-12 p40) mAb to take advantage on its capacity to decrease IL-18 levels via indirect effects on pro-ILi8 production. In both cases, a decrease in intestinal inflammation was observed with such treatment. In the case of the third XLA patient similar analysis of peripheral blood and intestinal tissue revealed an as yet unexplained increase in both IFN-gamma and IL-17 production. Whatever the casuse, treatment with Ustekinumab led to a significant decrease in intestinal inflammation.