Clinical Studies of Inflammatory Bowel Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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 have conducted studies of IBD associated with LRRK2 risk polymorphisms as described in relation to laboratory studies in an accompanying Annual Report. In these studies we have established that these polymorphisms are associated with increased levels of LRRK2 and this elevation in mice results in more severe induced colitis in the DSS-colitis model. In addition, we have shown that cells derived from patients who do not bear the LRRK2 risk polymorphism exhibit reduced pro-inflammatory cytokine responses in vitro when their cells are exposed to inhibitors of the kinase activity of LRRK2. Finally, we have established that induced colitis of normal mice or mice with elevated levels of LRRK2 is inhibited by administration of various LRRK2 inhibitors. These observations suggest that treatment of patients with inhibitors of LRRK2 can have a therapeutic effect in all patients with IBD regardless of their LRRK2 status. Currently, we are collaborating with Dr. Inga Peter and her colleagues at the Mt. Sinai Medical Center in New York focused on the development and testing of new gut-restricted LRRK2 inhibitors. In this period, we are conducting 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 changes in clinical parameters correlated with a 10-fold increase in Foxp3+ T regulatory cells (Tregs) co-expressing RORgammat in the case of one patient but not in the other patient. These Treg changes correlated with the level of gut inflammation at the end of vorinostat treatment phase (week 12) noted upon endoscopic evaluation. 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. 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 only moderately reduced 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 for indirect effects on IL-18. In both cases, a decrease in intestinal inflammation was observed with such treatment. In the case of the third XLA patient similar analysis was performed on peripheral blood and intestinal tissue with an increase in IFN-gamma and IL-17 observed. Treatment with Ustekinumab led to a significant decrease in intestinal inflammation.