Biomedical subjects

Michael C Young

Publications and source records attributed to Michael C Young.

3 recordsLinked to original sources

PubMed2024

Targeting peptide antigens using a multiallelic MHC I-binding system.

Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.

Humans↗

PubMed2024

Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.

Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.

Interleukin-2↗

PubMed2005

Administration of epinephrine for life-threatening allergic reactions in school settings.

OBJECTIVE: Although the potential for life-threatening allergic reactions in children is a significant health concern for schools, there is little information about the circumstances surrounding anaphylactic events that occur in schools. The objectives of this study were to determine the incidence of anaphylaxis in schools, describe the circumstances around anaphylactic events, assess practices that are used to manage students with life-threatening allergies, and identify opportunities for improvement. METHODS: A total of 109 school districts in Massachusetts completed an Epinephrine Administration Form whenever epinephrine was administered at school. Data were collected from September 2001 to August 2003. RESULTS: Forty-eight school districts reported a total of 115 administrations of epinephrine during the 2-year reporting period. In 24% of the cases, the individual was not known to have a life-threatening allergy. Almost one third (31%) of the students who received epinephrine had allergies to multiple substances, and one quarter (25%) had an allergy to peanuts or tree nuts only. Twenty-two (19%) cases occurred outside the school building on the playground, traveling to and from school, or on field trips. The administration of epinephrine most often occurred in the health office by a registered nurse. The average time from onset of symptoms to administration of epinephrine was 10 minutes. In 92% of the cases, the student was transported to a medical facility via the emergency medical system. CONCLUSIONS: Anaphylactic reactions in schools, although not frequent, are not uncommon events. A systematic review of anaphylactic events that required epinephrine administration identified opportunities for improvement in the treatment of students with life-threatening allergies.

Anaphylaxis↗