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 and new research studies involving both patients with inflammatory bowel disease, 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 detail in a previous annual report. In these studies we have established that the polymorphism is associated with increased levels of LRRK2 and this elevation is accompanied by increased gut inflammation in an induced colitis model. Several observations derived from these studies have direct clinical significance. The first is 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. The second is 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 have continued a study 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 now obtained NIAID IRB and FDA approval. The study will ultimately enroll 20 patients who have failed other forms of Crohn's disease therapy; these patients will undergo a wide array of studies 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 suggest that vorinostat may be a new avenue of treatment for IBD patients but additional patient studies are required 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 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, two patients (one adult and one pediatric patient) with X-linked agammaglobulinemia and unresponsive colitis have been entered into this study. Both patients had previously undergone bowel resection due to refractory intestinal inflammation. The immune workup revealed increased IL-1beta and IL-18 generation by peripheral blood macrophages indicative of excessive NLRP3 inflammasome activity as predicted bt the studies previously conducted in mice. To address the excessive IL-1beta production both patients have been subsequently started on Anakinra and have exhibited partial amelioration of colitis. However, in the case of the pediatric patient improvement was not considered sufficient possibly due to the unchecked effect of IL-18 production. Consequently, ustekinumab (ant-IL-12p40) was added to his regimen after which a significant decrease in symptoms (i.e., abdominal pain and diarrhea) was observed.