R01AI187989

Evaluation of the mechanisms underlying induction and maintenance immunosuppression impact on T cell function after kidney transplantation - Abstract

Antithymocyte globulin (ATG) is a lymphodepleting induction immunosuppression used in approximately 30% of all kidney transplants, associated with decreased rates of rejection but increased rates of infection after kidney transplantation (KTX).

Despite many years of use, the mechanism of action behind the observation remains unknown.

A current unmet need in the field of transplantation, therefore, is understanding the impact of ATG induction and the concomitant maintenance immunosuppression medications to guide candidate selection and post-transplant management of immunosuppression.

Our R21-derived data demonstrated an association between epigenetic changes in PBMC and incidence of infection after kidney transplantation.

We have additionally observed that ATG causes a distinct impact on differential methylation at regions related to T cell differentiation and activation using bulk DNA methylation approaches, and that ATG differentially impacts CD4 memory T cells, CD8 terminally differentiated T cells, and senescent T cells compared with non-ATG induction.

However, we lack information at the single cell level relating to epigenetic, transcriptional, and immune phenotype changes.

We also lack information regarding the longitudinal relationship of epigenetic and transcriptional changes and the impact of ATG on T cell function and T cell receptor (TCR) repertoire.

We hypothesize that ATG, compared with non-ATG induction, will alter the epigenetic and transcriptional landscape after KTX, and that these changes will be associated with significant differences in immune phenotype, with expansion of memory CD4 and senescent CD8 T cells.

Using a single cell analysis approach, we will analyze regions of differential chromatin accessibility and gene expression as well as cell surface proteins to determine the mechanism impact of ATG and maintenance immunosuppression.

We hypothesize that ATG will change T cell phenotype and function measured by cytokine secretion in response to clinically relevant infectious antigens and decrease TCR repertoire post-KTX, compared with patients receiving non-ATG induction.

We will test this hypothesis using antigen stimulation and measure cytokine release and TCR repertoire in the ATG versus non-ATG group.

Our overarching goal is to understand the mechanism behind ATG-driven epigenetic changes on T cells by quantifying alterations to the epigenome and transcriptome in parallel with evaluating measures of T cell function.

Defining mechanisms at a molecular level will provide insight for development of tools for candidate selection and patient risk stratification.

We will take advantage of biobanked specimens of pre- and post-KTX patients in a cohort with previously collected outcome data at a granular level, including demographic and clinical details.

We will develop a comprehensive understanding of how immunosuppression impacts epigenetic and transcriptional regulation of T cell function, a crucial component of the immune system controlling development of infection.

Ultimately, this information can be applied to guide immunosuppression and improve patient outcomes after KTX.

Los Angeles University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Los Angeles, California 90095 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)