RESUMO
The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor-induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1-dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.
Assuntos
Mucosa Intestinal/efeitos dos fármacos , Timalfasina/metabolismo , Timalfasina/farmacologia , Animais , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismo , Timalfasina/fisiologia , Timosina/metabolismo , Timosina/fisiologiaRESUMO
INTRODUCTION: Thymosin alpha 1 (Ta1) is a natural occurring peptide hormone that is crucial for the maintenance of the organism homeostasis. It has been chemically synthesized and used in diseases where the immune system is hindered or malfunctioning. AREAS COVERED: Many clinical trials investigate the Ta1 effects in patients with cancer, infectious diseases and as a vaccine enhancer. The number of diseases that could benefit from Ta1 treatment is increasing. To date, questions remain about the physiological basal levels of Ta1 and the most effective dose and schedule of treatment. Evidence is growing that diseases characterized by deregulation of immune and/or inflammatory responses are associated with serum levels of Ta1 significantly lower than those of healthy individuals: to date, B hepatitis, psoriatic arthritis, multiple sclerosis and sepsis. The sputum of cystic fibrosis patients contains lower levels of Ta1 than healthy controls. These data are consistent with the role of Ta1 as a regulator of immunity, tolerance and inflammation. EXPERT OPINION: Low serum Ta1 levels are predictive and/or associated with different pathological conditions. In case of Ta1 treatment, it is crucial to know the patient's baseline serum Ta1 level to establish effective treatment protocols and monitor their effectiveness over time.
Assuntos
Doença , Homeostase/fisiologia , Timalfasina/sangue , Adjuvantes Imunológicos/sangue , Adjuvantes Imunológicos/uso terapêutico , Doenças Transmissíveis/sangue , Doenças Transmissíveis/tratamento farmacológico , Doença/etiologia , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Humanos , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/terapia , Sepse/sangue , Sepse/tratamento farmacológico , Timalfasina/fisiologia , Timalfasina/uso terapêutico , Vacinas/uso terapêuticoRESUMO
INTRODUCTION: Thymosin alpha 1 (Tα1) is a naturally occurring polypeptide of 28 amino acids, whose mechanism of action is thought to be related to its ability to signal through innate immune receptors. Tα1 (ZADAXIN®) is used worldwide for treating viral infections, immunodeficiencies, and malignancies. Owing to its ability to activate the tolerogenic pathway of tryptophan catabolism - via the immunoregulatory enzyme indoleamine 2,3-dioxygenase - Tα1 potentiates immune tolerance mechanisms, breaking the vicious circle that perpetuates chronic inflammation in response to a variety of infectious noxae. AREAS COVERED: Tα1 has never been studied in Cystic fibrosis (CF) in which the hyperinflammatory state is associated with early and nonresolving activation of innate immunity, which impairs microbial clearance and promotes a self-sustaining condition of progressive lung damage. Optimal CF treatments should, indeed, not only rescue CF transmembrane conductance regulator protein localization and functionality but also alleviate the associated hyperinflammatory pathology. Because of the inherent complexity of the pathogenetic mechanisms, a multidrug approach is required. EXPERT OPINION: By providing a multipronged attack against CF, i.e. restraining inflammation and correcting the basic defect, Tα1 favorably opposed CF symptomatology in preclinical relevant disease settings, thus suggesting its possible exploitation for 'real-life' clinical efficacy in CF. This could represent a major conceptual advance in the CF field, namely the proposal of a drug with the unique activity to correct CFTR defects through regulation of inflammation.