In the past year the Mucosal Immunity Section has been engaged in a number of research studies involving both inflammatory bowel disease and common variable immunodeficiency. In the area of IBD, we have conducted studies of IBD associated with LRRK2 risk polymorphisms, as described in detail in another 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 driven by Dectin-1 induced NF-kappaB responses. 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 cells are exposed to antibodies that inhibit the kinase activity of LRRK2. The second is that induced colitis of normal mice is inhibited by administration of anti-LRRK2. These observations suggest that treatment of patients with anti-LRRK2 can have a therapeutic effect in all patients with IBD regardless of their LRRK2 status. In other IBD studies we have investigated Crohn's disease-like colitis occurring in patients with chronic granulomatous disease (CGD). These studies include the evaluation of cytokine production in the inflamed mucosa of CGD patients. In the studies conducted so far, Crohn's disease in CGD patients and conventional patients appear to be quite similar. In addition, even CGD patients without symptoms of overt Crohn's disease exhibit immunologic abnormalities suggest the presence of covert disease. This has led us to conclude that CGD is, in effect, a risk factor for the development of Crohn's disease that manifests itself in all CGD patients. Finally, we have designed and written a clinical protocol for a study of the safety and and immunologic effects of treatment of patients with moderately severe patients with Crohn's disease with vorinostat, an HDAC inhibitor. This clinical trial will be partially funded by a CRADA with Merck and will involve 26 patients who have failed other forms of Crohn's disease therapy. A wide array of studies to evaluate the immunologic effects of HDAC inhibitor therapy will be performed, including extensive studies of the drug's effect on regulatory T cells present in gut biopsy specimens. Currently, the Clinical Protocol has been written and awaits scientific and clinical approval as well as FDA approval. In the area of CVID we have continued to focus on 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 in the Laboratory of Cellular and Molecular Immunology in studies of CVID that included microarray analyses of biopsy tissue of CVID patients with enteropathy showing that CVID enteropathy is characterized by up-regulation of genes related to various interferons. Based on this prior work, we have applied for and have obtained a U01 NIH cooperative research grant (PAR-13-029) with Drs. Morgan and Shulzhenko (now at Oregon State University) to expand on these findings. This Grant is entitled Anti-IL-12p40 Treatment of CVID Enteropathy: Gene Expression and Microbiota Analysis, and is centered around a clinical study of the safety and efficacy of a FDA-approved monoclonal anti-IL-12p40 in the treatment of CVID enteropathy. In addition, this Grant includes a study of the effect of this biologic agent on gene expression of inflammatory cytokines and on the microbiota in patients. In an initial phase of these studies, we have treated three patients with CVID enteropathy with a single dose of anti-IL-12p40 (270mg SC Stelara)and have found that in two of the three patients there was clinical improvement with respect to diarrhea. In one of the two patients, there was long-term and dramatic cessation of diarrhea, whereas in another patient diarrhea persisted at a reduced level. However, improvement in objective measure of malabsorption such as stool fat assessment was observed in none of the patients. As a result of this experience we believe that a greater therapeutic effect can be obtained with a multiple dose regimen consisting of 270mg induction dose followed by two addition 180mg doses over a six month period and have applied to the NIAID IRB for permission to treat patients in this manner. Meanwhile stool and tissue specimens of CVID patients with and without enteropathy have been sent to Drs. Morgun and Shulzhenko at Oregon State University for microbiome analysis before and after anti-IL-12p40 treatment as well as identification of a possible organism causing the enteropathy. A major outcome of this collaborative study has emerged from analysis of patient immunoglobulin levels in gut specimens. We have found that those patients with enteropathy have little or no expression of IgA in intestinal biopsies whereas those patients without enteropathy have only moderately reduced levels of IgA. Moreover, this deficiency does not extend to mucosal IgG levels. This finding indicates that enteropathy occurs in the subset of CVID patients with severe mucosal B cell immunodeficiency affecting the mucosal immunoglobulin, IgA. A second major outcome from these studies is the finding the duodenal specimens from patients with enteropathy are associated with A. baumanii, an organism that could be inducing the high IFN-gamma production associated with this abnormality. In other studies of CVID patients we have continued to evaluate the course and characteristics of nodular regenerative hypeplasis (NRH), a complication of CVID that we have defined previously. The focus of the present study was the occurrence or reoccurrence of NRH following liver transplantation. In one patient with CVID likely due to GATA2 deficiency successful liver transplantation for severe inflammatory hepatitis and liver decompensation was followed by re-occurrence of hepatitis now accompanied by NRH. In a second patient with CVID associated with Kabuki syndrome, liver transplantation for liver decompensation due to severe NRH was followed by re-appearance of NRH in the transplanted liver. The disease course displayed by these patients indicates that NRH is due an as yet ill-defined immunologic mechanism driven by the underlying immunodeficiency state and that liver transplantation should be followed by bone marrow transplantation to address the CVID and recurrent NRH.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code
Watanabe, Tomohiro; Yamashita, Kouhei; Arai, Yasuyuki et al. (2017) Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-? and IL-33 Produced by Plasmacytoid Dendritic Cells. J Immunol 198:3886-3896
Arai, Yasuyuki; Yamashita, Kouhei; Kuriyama, Katsutoshi et al. (2015) Plasmacytoid Dendritic Cell Activation and IFN-? Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis. J Immunol 195:3033-44
Strober, Warren (2015) Trypan Blue Exclusion Test of Cell Viability. Curr Protoc Immunol 111:A3.B.1-3
Kiesler, Patricia; Fuss, Ivan J; Strober, Warren (2015) Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol 1:154-170
Fichtner-Feigl, Stefan; Kesselring, Rebecca; Strober, Warren (2015) Chronic inflammation and the development of malignancy in the GI tract. Trends Immunol 36:451-9
Fichtner-Feigl, Stefan; Kesselring, Rebecca; Martin, Maria et al. (2014) IL-13 orchestrates resolution of chronic intestinal inflammation via phosphorylation of glycogen synthase kinase-3?. J Immunol 192:3969-80
Fuss, Ivan J; Joshi, Bharat; Yang, Zhiqiong et al. (2014) IL-13R?2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. Gut 63:1728-36
Fuss, Ivan J; Friend, Julia; Yang, Zhiqiong et al. (2013) Nodular regenerative hyperplasia in common variable immunodeficiency. J Clin Immunol 33:748-58
Hueber, Wolfgang; Sands, Bruce E; Lewitzky, Steve et al. (2012) Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61:1693-700
Read, Sarah W; Ciccone, Emily J; Mannon, Peter J et al. (2011) The effect of intermittent IL-2 therapy on CD4 T cells in the gut in HIV-1-infected patients. J Acquir Immune Defic Syndr 56:340-3

Showing the most recent 10 out of 18 publications