Immunobiology of chimeric antigen receptor T cells and novel designs

Advances in the development of immunotherapies have offered exciting new options for the treatment of malignant diseases that are refractory to conventional cytotoxic chemotherapies. The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated dramatic results in clinical trials and highlights the promise of novel immune‐based approaches to the treatment of cancer. As experience with CAR T cells has expanded with longer follow‐up and to a broader range of diseases, new obstacles have been identified which limit the potential lifelong benefits of CAR T cell therapy. These obstacles highlight not only the gaps in knowledge of the optimal clinical application of this “living drug”, but also gaps in our understanding of the fundamental biology of CAR T cells themselves. In this review, we discuss the obstacles facing CAR T cell therapy, how these relate to our current understanding of CAR T cell biology and approaches to enhance the clinical efficacy of this therapy.     

Cytokine-targeted therapy for the management of solid organ transplant recipients

IntroductionThe number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects.BodyCytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn’s, and multiple sclerosis.ConclusionThis article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.     

Wohlfahrtiimonas chitiniclastica: Two Clinical Cases and a Review of the Literature

Wohlfahrtiimonas chitiniclastica has been identified as an emerging pathogen predominantly associated with cutaneous myiasis and poor hygiene. Traditional biochemical methods can be unreliable and misleading when identifying this organism, and modern molecular techniques are often necessary for high-confidence identification. There have been very few cases of human infection with W. chitiniclastica reported in the literature. We present two recent cases identified at the University of Kentucky Medical Center (a male with myiasis related to gangrene and an elderly female with a left-leg wound and myiasis), both of which were identified using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) for identification, and describe the clinical and microbiologic characteristics associated with this microorganism.     

Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions

BackgroundDendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses.MethodsThe effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined.ResultsDexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1β and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-β). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4⁺ T cell proliferation and cytokine release (IFNγ, TNF-α and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity.ConclusionsThese findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.     

The impact of descriptive norms on motivation to participate in cancer screening – Evidence from online experiments

ObjectiveThe current study tested in two online experiments whether manipulating normative beliefs about cancer screening uptake increases intention to attend colorectal screening among previously disinclined individuals.Methods2461 men and women from an Internet panel (Experiment 1 N = 1032; Experiment 2, N = 1423) who initially stated that they did not intend to take up screening were asked to guess how many men and women they believe to get screened for colorectal cancer. Across participants, we varied the presence/absence of feedback on the participant’s estimate, as well as the stated proportion of men and women doing the screening test.ResultsAcross the two experiments, we found that receiving one of the experimental messages stating that uptake is higher than estimated significantly increased the proportion of disinclined men and women becoming intenders. While, we found a positive relationship between the communicated uptake and screening intentions, we did not find evidence that providing feedback on the estimate has an added benefit.ConclusionScreening intention can be effectively manipulated through a high uptake message.Practice implicationsCommunication of high screening uptake is an easy and effective way to motivate disinclined individuals to engage in colorectal cancer screening.     

An emerging novel virus: Atypical porcine pestivirus (APPV)

Emerging porcine pestivirus diseases frequently challenge prevention and control strategies in the swine industry. Over the past decade, a few novel pestiviruses have been identified in pigs. This article focuses on the recently emerging atypical porcine pestivirus (APPV) that potentially threatens global swine herd health security. The virus was first identified in 2016, in the United States and thereafter, accumulated evidence shows that it is currently distributed in three continents. The clinical presentation of APPV‐infected pigs is characterized by congenital tremor (CT) type A‐II in piglets, while adult pigs may become persistent carriers and shedders. Here, a literature review is conducted to summarize the published findings in the virus genomic biology, transmission, epidemiology, pathogenesis, and diagnosis, which would shed light on acceleration of development of anti‐APPV strategies.     

Effects of of habitats and pesticides on aerobic capacity and survival of soil fauna

Faunal health is largely dependent on their soil environment and available litter quality. So the effects of different soil habitats and pesticides on citrate synthase (CS) activity of soil fauna and its population were studied. Methods The soil animals were collected from different pedoecosystems for habitat study. Whereas Vigna radiata based system was selected for pesticidal observations. The field was divided into five equal plots for control and treatment of γ-BHC, quinalphos, carbaryl and cypermethrin. Soil fauna was collected by quadrat method and extracted by Tullgren funnel. Individuals of a species having similar sizes were collected for the estimation of CS activity. They were homogenized and fractions were obtained by differential centrifugation. The activity of CS was assayed spectrophotometrically. Results Citrate synthase (CS) activity of beetle (Rasphytus fregi), woodlouse (PorceUio laevis) and centipede (Scolopendra morsitans) varied significantly with respect to changes in different soil habitats. Though the CS activity of R. fregi, P. laevis, and S. morsitans differed among themselves but the highest activity of CS in these animals was in V. radiata and lowest in A. nilotica based pedoecosystem. The aerobic capacity of centipede was maximum followed by woodlouse and beetle. The treatment of γ-BHC, quinalphos, carbaryl and cypermethrin significantly reduced the CS activity of these animals. γ-BHC showed maximum reduction in CS activity indicating highly toxic effect of organochlorine on aerobic metabolism of soil fauna. However, minimum reduction was obseryed in response to carbaryl (in beetle) or cypermethrin (in woodlouse/centipede) leading to impairment of aerobic capacity. The differences in pesticide effects might be assigned to the differences in chemical nature of pesticides and their interactions with below-ground fauna. Treatment ofγ-BHC and quinalphos reduced the population of Acari, Coleoptera, Collembola, other arthropods as well as total soil fauna. Acari was least affected by γ-BHC and maximally affected (72%) in response to quinalphos. The effect of γ-BHC was fairly similar on Coleoptera, Collembola, other arthropod and total soil fauna suggesting almost similar sensitivity to this pesticide. Likewise, quinalphos was similarly effective on Collemobola and other soil arthropods. Application of carbaryl decreased Acari and Coleoptera population but increased Collembola, other arthropods and total faunal populations. However, application of cypermethrin significantly reduced the population of Acari, Coleoptera, Collembola and total soil fauna and increased the population of other soil arthropods. In both the cases, acarine population was least affected. Conclusion The observations show the habitat-specific variation in aerobic capacity of soil fauna. However, pesticide-dependent loss in population might be due to impairment of aerobic capacity of soil inhabiting animals in desert.