ABSTRACT
Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Enterocolitis/chemically induced , Neoplasms/drug therapy , Societies, Medical/organization & administration , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/toxicity , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/toxicity , Consensus , Endoscopy/methods , Endoscopy, Digestive System/methods , Enterocolitis/drug therapy , Enterocolitis/metabolism , Gastroenterology/organization & administration , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/diagnostic imaging , Gastrointestinal Diseases/pathology , Guidelines as Topic , Humans , Infliximab/therapeutic use , Lactoferrin/metabolism , Leukocyte L1 Antigen Complex/metabolism , Patient Care Management/methods , Tumor Necrosis Factor-alpha/antagonists & inhibitors , United Kingdom/epidemiologySubject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Resistance, Neoplasm , Gastrointestinal Neoplasms/genetics , Gastrointestinal Stromal Tumors/genetics , Germ-Line Mutation , Intestine, Small , Mastocytosis/genetics , Piperazines/pharmacology , Proto-Oncogene Proteins c-kit/genetics , Pyrimidines/pharmacology , Adult , Biomarkers, Tumor/analysis , Exons , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/complications , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/surgery , Humans , Imatinib Mesylate , Immunohistochemistry , Intestine, Small/pathology , Intestine, Small/surgery , Male , Mastocytosis/complications , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/analysis , Tomography, X-Ray ComputedABSTRACT
The functions of OmpATb, the product of the ompATb gene of Mycobacterium tuberculosis and a putative porin, were investigated by studying a mutant with a targeted deletion of the gene, and by observing expression of the gene in wild-type M. tuberculosis H37Rv by real-time polymerase chain reaction (PCR) and immunoblotting. The loss of ompATb had no effect on growth under normal conditions, but caused a major reduction in ability to grow at reduced pH. The gene was substantially upregulated in wild-type bacteria exposed to these conditions. The mutant was impaired in its ability to grow in macrophages and in normal mice, although it was as virulent as the wild type in mice that lack T cells. Deletion of the ompATb gene reduced permeability to several small water-soluble substances. This was particularly evident at pH 5.5; at this pH, uptake of serine was minimal, suggesting that, at this pH, OmpATb might be the only functioning porin. These data indicate that OmpATb has two functions: as a pore-forming protein with properties of a porin, and in enabling M. tuberculosis to respond to reduced environmental pH. It is not known whether this second function is related to the porin-like activity at low pH or involves a completely separate role for OmpATB. The involvement with pH is likely to contribute to the ability of M. tuberculosis to overcome host defence mechanisms and grow in a mammalian host.
