Inflammatory bowel diseases (IBDs) comprise a group of chronic gastrointestinal disorders characterized by periods of relapse and remission. The mainstay of treatment is medical, involving medications such as steroids, immune modulators, monoclonal antibodies (categorized as biologics), and small molecules. These medications can provide profound therapeutic benefits, but they can also cause severe and irreversible toxicities. Clinicians may utilize laboratory tests in the diagnosis and management of IBD including assessment of disease activity, monitoring medication response or toxicity, surveillance of infectious complications, and detection of nutritional deficiencies. Routine use of laboratory tests may help clinicians avoid reactivation of life-threatening infections such as tuberculosis or hepatitis B virus upon initiation of immune suppressive therapy. They can also be used to detect vitamin deficiencies such as B12 deficiency, which has the potential to cause irreversible neurologic damage. While some laboratory tests constitute established practices, the utility of newer tests such therapeutic drug monitoring (TDM) in the era of biologics is an evolving topic. Although clinical assessment with imaging, endoscopic, and histopathological examination is standard practice, laboratory tests serve as valuable adjuncts. We aim to explore the broad range of laboratory tests available to clinicians and to summarize their application in the current management of IBD in daily clinical practice, with special attention to updates in therapeutic drug monitoring.

Helminths are multicellular invertebrates that colonize the gut of many vertebrate animals including humans. This colonization can result in pathology, which requires treatment. It can also lead to a commensal and possibly even a symbiotic relationship where the helminth and the host benefit from each other's presence. Epidemiological data have linked helminth exposure to protection from immune disorders that include a wide range of diseases, such as allergies, autoimmune illnesses, and idiopathic inflammatory disorders of the gut, which are grouped as inflammatory bowel diseases (IBD). Treatment of moderate to severe IBD involves the use of immune modulators and biologics, which can cause life-threatening complications. In this setting, their safety profile makes helminths or helminth products attractive as novel therapeutic approaches to treat IBD or other immune disorders. Helminths stimulate T helper-2 (Th2) and immune regulatory pathways, which are targeted in IBD treatment. Epidemiological explorations, basic science studies, and clinical research on helminths can lead to the development of safe, potent, and novel therapeutic approaches to prevent or treat IBD in addition to other immune disorders.

Abstract Recipient T cells can aggravate or regulate lethal and devastating graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In this context, we have shown before that intestinal immune conditioning with helminths is associated with survival of recipient T cells and Th2 pathway–dependent regulation of GVHD. We investigated the mechanism of survival of recipient T cells and their contribution to GVHD pathogenesis in this helminth infection and BMT model after myeloablative preparation with total body irradiation in mice. Our results indicate that the helminth-induced Th2 pathway directly promotes the survival of recipient T cells after total body irradiation. Th2 cells also directly stimulate recipient T cells to produce TGF-β, which is required to regulate donor T cell–mediated immune attack of GVHD and can thereby contribute to recipient T cell survival after BMT. Moreover, we show that recipient T cells, conditioned to produce Th2 cytokines and TGF-β after helminth infection, are fundamentally necessary for GVHD regulation. Taken together, reprogrammed or immune-conditioned recipient T cells after helminth infection are crucial elements of Th2- and TGF-β–dependent regulation of GVHD after BMT, and their survival is dependent on cell-intrinsic Th2 signaling.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.

Parasites have coevolved with humans. Several of them colonize the human body and establish a symbiotic relationship. Other parasites cause severe and lethal diseases. Prevalence of parasitic infections is decreased in highly industrialized countries, largely due to enforced hygienic practices. In contrast, parasites cause significant morbidity and mortality in parts of the world with barriers to effective public hygiene. Some parasites have emerged as potent pathogens in specific patient populations, such as immune suppressed individuals, regardless of sanitation. This article reviews common parasites encountered in clinical practice and, in the setting of host-parasite symbiosis, discusses their immune regulatory role.

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6‐signaling. We examined the importance of intact T cell Stat6 signaling on helminth‐induced suppression of murine colitis that results from T cell transfer into immune‐deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN‐γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN‐γ co‐expression by IL‐17 + T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection‐associated regulation of pathogenic intestinal inflammation.

Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation-mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane-bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10-/- /Rhbdf2-/- mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10-/- /Rhbdf2-/- mice correlated with a dysbiotic gut microbiota and elevated Th1-associated immune responses with increased interferon gamma and IL2 production. In addition, Il10-/- /Rhbdf2-/- mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2-/- mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium-induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.

Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn’s disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-beta and is associated with TGF-beta-dependent in vivo expansion of Foxp3(+) regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-beta-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-beta secretion, TGF-beta-dependent expansion of Foxp3(+) Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-beta. In contrast, TGF-beta is not necessary for GATA3 expression by Foxp3(+) Tregs or by Foxp3(-) CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-beta generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.

BackgroundPatients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA.AimsWe investigated the lung response to bacterial endotoxin in colitic mice.MethodsRag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3weeks later.ResultsColitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c(+), CD8(+) cells bound and responded to non-systemic antigens from gut-localized microbiota and had higher expression of TLR4.ConclusionsColitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4(+) cells. CD11c(+), CD8(+) cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation.