Biological Therapies and Tuberculosis Infection in Dermatology

After contact with a case of transmissible tuberculosis (TB), some of the exposed individuals may be infected and develop an immune reaction against Mycobacterium tuberculosis (Mtb), the causative agent of the disease. The replication of mycobacteria is usually stopped within cellular structures called granulomas, whose integrity relies on a complex interplay between cells and cytokines, the most prominent of them being TNF. In case of deficiency or inhibition of the activity of TNF, the granulomas may disrupt and release the surviving mycobacteria which may multiply, disseminate and lead to active TB disease. Several immune-mediated inflammatory diseases, among which rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis and psoriasis can be treated by biological therapies acting by the inhibition of TNF or cytokines like IL-17 and IL-23. If these therapies, in particular TNF-inhibitors, are administered to people infected by Mtb, there is a risk of decreasing the integrity of granulomas and increasing the probability of mutiplication of mycobacteria and TB reactivation. Therefore, in persons with rheumatological, gastro-enterological and dermatological diseases candidate to biological therapies there is a general recommendation of screening for TB infection (TBI) at baseline. The screening should include also a search for history of prior TB or contact with TB, a test for the presence of TBI, and if scored positive, a chest X-Ray

Vaccination, Immunity and Breakthrough: Quantitative Effects in Individual Immune Responses Illustrated by a Simple Kinetic Model

The personal risks of infection, as well as the conditions for achieving herd immunity, are strongly dependent on an individual’s response to the infective agents on the one hand, and the individual’s reactions to vaccination on the other hand. The main goal of this work is to illustrate the importance of quantitative individual effects for disease risk in a simple way. The applied model was able to illustrate the quantitative effects, in the cases of different individual reactions, after exposition to viruses or bacteria and vaccines. The model was based on simple kinetic equations for stimulation of antibody production using different concentrations of the infective agent, vaccine and antibodies. It gave a qualitative explanation for the individual differences in breakthrough risks and different requirements concerning a second, third or further vaccinations, reconsidering different efficiencies of the stimulation of an immune reaction.

Mobilizing Endogenous Repair Through Understanding Immune Reaction With Biomaterials

With few exceptions, humans are incapable of fully recovering from severe physical trauma. Due to these limitations, the field of regenerative medicine seeks to find clinically viable ways to repair permanently damaged tissue. There are two main approaches to regenerative medicine: promoting endogenous repair of the wound, or transplanting a material to replace the injured tissue. In recent years, these two methods have fused with the development of biomaterials that act as a scaffold and mobilize the body’s natural healing capabilities. This process involves not only promoting stem cell behavior, but by also inducing activity of the immune system. Through understanding the immune interactions with biomaterials, we can understand how the immune system participates in regeneration and wound healing. In this review, we will focus on biomaterials that promote endogenous tissue repair, with discussion on their interactions with the immune system.

Intestinal Macrophage Autophagy and its Pharmacological Application in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory disorders. IBD is regarded as a severe healthcare problem worldwide, with high morbidity and lethality. So far, despite of numerous studies on this issue, the specific mechanisms of IBD still remain unclarified and ideal treatments are not available for IBD. The intestinal mucosal barrier is vital for maintaining the function of the intestinal self-defensive system. Among all of the components, macrophage is an important one in the intestinal self-defensive system, normally protecting the gut against exotic invasion. However, the over-activation of macrophages in pathological conditions leads to the overwhelming induction of intestinal inflammatory and immune reaction, thus damaging the intestinal functions. Autophagy is an important catabolic mechanism. It has been proven to participate the regulation of various kinds of inflammation- and immune-related disorders via the regulation of inflammation in related cells. Here in this paper, we will review the role and mechanism of intestinal macrophage autophagy in IBD. In addition, several well-studied kinds of agents taking advantage of intestinal macrophage autophagy for the treatment of IBD will also be discussed. We aim to bring novel insights in the development of therapeutic strategies against IBD.

CTIM-03. AUTOLOGOUS ADOPTIVE IMMUNE-CELL THERAPY ELICITED A DURABLE RESPONSE WITH ENHANCED IMMUNE REACTION SIGNATURES IN PATIENTS WITH RECURRENT GLIOBLASTOMA: AN OPEN LABEL, PHASE I/IIA TRIAL

Glioblastoma multiforme (GBM) is an aggressive malignancy classified by the World Health Organization as a grade IV glioma. Despite the availability of aggressive standard therapies, most patients experience recurrence, for which there are currently no effective treatments. We aimed to conduct a phase I/IIa clinical trial to investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM. This study was a single-arm, open-label, investigator-initiated trial on 14 patients recruited between 2013 and 2017. The immune cells were administered via intravenous injection 24 times at 2-week intervals after surgical resection or biopsy. The safety and clinical efficacy of this therapy was examined by assessing adverse events and comparing 2-year overall survival (OS). Transcriptomic analysis of tumor tissues was performed using NanoString to identify the mechanism of therapeutic efficacy. No grade 4 or 5 severe adverse events were observed. The most common treatment-related adverse events were grade 1 or 2 in severity. The most severe adverse event was grade 3 fever. Median OS was 22.5 months, and the median progression-free survival was 10 months. Five patients were alive for over 2 years and showed durable response with enhanced immune reaction transcriptomic signatures without clinical decline until the last follow-up after completion of the therapy. In conclusion, autologous adoptive immune-cell therapy was safe and showed durable response in patients with enhanced immune reaction signatures. This therapy may be effective for recurrent GBM patients with high immune response in their tumor microenvironments. Trial registration: The Korea Clinical Research Information Service database: KCT0003815, Registered 18 April 2019, retrospectively registered.

SARS-CoV-2 infection induces cross-reactive autoantibodies against angiotensin II

Patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV- 2) can experience life-threatening respiratory distress, blood pressure dysregulation and thrombosis. This is thought to be associated with an impaired activity of angiotensin- converting enzyme-2 (ACE-2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized COVID-19 patients developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or RBD, to which they can cross- bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.

1394. Autochthonous Leprosy in Missouri

Background Introduction: Leprosy (Hansen’s disease) is a chronic granulomatous infection of the skin/peripheral nerves caused by Mycobacterium leprae. Of 216 new cases reported in the US in 2019, 70% were in FL, LA, TX, HI, CA, GA and NY. Leprosy is considered a zoonosis in the southern US with the nine-banded armadillo as a reservoir. There have been no reported autochthonous leprosy cases in Missouri. Methods Case: 55 y/o previously healthy male noted a new rash on his arm 2 years ago. Over time it spread to his extremities/torso. Skin biopsy showed a granulomatous infiltrate, suspected granuloma annulare, but it progressed despite appropriate therapy. He noted progressive numbness of the affected areas of skin and several regional nerve distributions. In the weeks prior to his initial visit he noted facial swelling, eyelid and ear induration, worsening fatigue, diffuse arthralgia, and some vision changes. His travel history is limited to Canada, Colorado and a brief vacation to the Texas/Mexico border (no notable outdoor exposure during the latter trip; no travel outside the country). He lives in rural Missouri where he is exposed to armadillos. His dogs frequently kill them and often bring them into the yard, rolling around on/in the dead carcasses which he disposes of. He typically wears gloves when handling them and has never consumed them. On exam he had diffuse purplish-red nummular infiltrated anesthetic papules and plaques diffusely distributed over the trunk and extremities. Distinct left ulnar neuropathy was noted. He exhibited leonine facies and infiltration of the bilateral helices. Repeat biopsy showed a granulomatous infiltrate with abundant acid-fast bacilli. DNA sequencing confirmed M. leprae. He was preventatively treated with prednisone and methotrexate to minimize immune reaction, and two weeks later began a regimen of monthly rifampin, minocycline, and moxifloxacin with an anticipated duration of 24 months. Results Diagnosis lepromatous leprosy with pre-treatment immune reaction. This is potentially the first case of autochthonous leprosy in Missouri. Providers should include Hansen’s disease in the differential diagnosis of patients with dermal eruption and cutaneous neurological symptoms to avoid delays in diagnosis/care. Disclosures All Authors: No reported disclosures

Synthesis and Characterization of Lanthanum Nanoparticles by Anethum Graveolens (Dill) Leaf Extract

Anethum Graveolens is a herb used extensively as an additive in chicken feed to help in enhancing the performance, immune reaction and fitness of broiler chickens. The herb consists of various volatile secondary metaboliteswhich are bioactive compounds which helps in their daily food regime. This present work is aimed atsynthesizing and characterizing Lanthanum-nanoparticles (LaNps) by using Anethum Graveolens (dill) leaf. LaNps has been synthesized by various methods and characterized by using UV-Vis spectral analysis, Fourier infra-red , X-ray diffraction and SEM analysis.