Alessandrini Laboratory

Overview

The Alessandrini Laboratory focuses on elucidating the mechanisms behind graft tolerance, utilizing three primary mouse models: spontaneous kidney allograft acceptance, mixed chimeras, and spontaneous tumor models. In synthesizing findings obtained from these models, we aim to identify the molecular and cellular components that contribute to the induction of-- what we dub--“defensive tolerance”. We employ and develop therapies to address key interactions within the model of defensive tolerance, designed to prolong tolerance.

Research Projects

Our research focuses on the mechanisms that drive the induction and maintenance of allograft tolerance and how these mimic establishment of the tumor immunoprivileged microenvironment. He has used the model of spontaneous kidney allograft acceptance to understand the pathways that drive natural tolerance of renal allotransplants (i.e., allograft acceptance without the use of immunosuppressive drugs). We have published several seminal papers that have clarified the pathways that determine tolerance of kidney grafts in mice and are guiding studies in large animals. Most recently, we have implored the use of single cell RNA sequencing (scRNAseq), transgenic recipients, and in vitro functional assays to elucidate these pathways and based on these new data, have developed a new concept in the field called ‘defensive tolerance’ wherein a tolerant allograft exhibits an active, intrinsic capacity to convert or inactivate infiltrating alloreactive leukocytes, and render them functionally innocuous. Our laboratory was one of the first to begin to analyze the nature of intra-graft immune cells in accepted and rejecting kidney transplants (Guinn et al., American Journal of Transplantation, 2023). Our paper in Journal of Clinical Investigation (Yokose et al., 2024) introduced the concept of defensive tolerance. We are currently analyzing other infiltrating immune cells and have data that show graft infiltrating pathogenic B cells and inflammatory myeloid cells are reprogrammed to regulatory-like B cells and non-inflammatory myeloid cells through the process of defensive tolerance. Recently, we have begun to analyze intra-graft immune cells in kidney grafts in non-human primate (NHP) and human kidney graft recipients. Preliminary data has shown that similar genes are differentially expressed in accepted and rejecting renal transplants in NHP and mice.

Research Team

Alessandro Alessandrini, PhD
Principal Investigator

Dr. Alessandrini is an Assistant Professor of Surgery at Harvard Medical School, the
Director of the Cell Signaling Laboratory within the Center for Transplantation Sciences at Massachusetts General Brigham.
aalessandrini@mgb.org

Koki Hayashi, MD, PhD
Post Doctoral Research Fellow

Dr. Hayashi joined the lab in 2024 from his role as a gastrointestinal surgeon at Keio University Hospital in Tokyo, Japan. He specializes in murine organ transplantation and bioinformatics.

Jenna Lancey, BA
Research Technician

Jenna is a graduate of Boston College, where she studied chemistry and history. She is interested in immunology, specifically the role of immunomodulatory molecule Fgl2 on transplant prolongation.

Sarah Rose Odutola
Undergraduate Student Researcher

Sarah Rose is an undergraduate at Harvard University, studying the effect of Fgl2 on prolonging graft survival.

Publications

View publications

Recent publications of note:

• Guinn MT, Szuter ES, Yokose T, Ge J, Rosales IA, Chetal K, Sadreyev RI, Cuenca AG, Kreisel D, Sage PT, Russell PS, Madsen JC, Colvin RB, Alessandrini A. Intragraft B cell differentiation during the development of tolerance to kidney allografts is associated with a regulatory B cell signature revealed by single cell transcriptomics. Am J Transplant. 2023 Sep;23(9):1319-1330. doi: 10.1016/j.ajt.2023.05.036. Epub 2023 Jun 8. PMID: 37295719; PMCID: PMC11232115.
• Yokose T, Szuter ES, Rosales I, Guinn MT, Liss AS, Baba T, Ruddy DA, Piquet M, Azzi J, Cosimi AB, Russell PS, Madsen JC, Colvin RB, Alessandrini A. Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance. J Clin Invest. 2024 Jun 18;134(16):e179709. doi: 10.1172/JCI179709. PMID: 38888968; PMCID: PMC11324304.
• Hayashi K, Yokose T, Lancey J, Szuter ES, Kwon B, Murillo F, Giarraputo A, Rosales I, Li W, Guinn MT, Cosimi G, Odutola SR, Kim J, Sage PT, Tarantino G, Huang A, Liu D, Effiom D, Boland GM, Cohen S, McCallion O, Issa F, Jordan C, Luo X, Liss AS, Ruddy DA, Piquet M, Russell PS, Colvin RB, Madsen JC, Cosimi AB, Kreisel D, Alessandrini A. Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance. Res Sq [Preprint]. 2025 Aug 18:rs.3.rs-7236564. doi: 10.21203/rs.3.rs-7236564/v1. PMID: 40894037; PMCID: PMC12393600.