Alpha2 macroglobulin (a2M) shares its cell surface receptor CD91 with the immunogenic heat shock proteins. Based on this observation we have tested and shown that mice immunized with a2M elicit T cell responses to peptides that are chaperoned by it. Preliminary studies presented for this project have shown that the engagement of CD91 by a2M and the ability of a2M to chaperone peptides are two key properties necessary for elicitation of the immune response. No other mechanistic procedure has been provided and the aims of this project are designed to understand first the interaction of these autologous proteins with antigen presenting cells to initiate the immune response and second what the physiological relevance of these proteins are in the elicitation of immune responses. A part of this project will test the harnessing of these immune responses for vaccine design targeting cancer and infectious disease. My primary short term goals also include studying a2M in context of other CD91 ligands such as the HSPs, and their various roles in cross-presentation and cross-priming. In this regard we have developed and published numerous tools necessary for this work: purification procedures for a2M and peptide antigens, procedures for the creation of a2M-peptide complexes, tumor rejection models in both prophylaxis and therapy and currently preparing CD91 deficient knock out mice. A long term goal is the translation of the basic research of my lab into clinical applications for the treatment of cancer and an understanding of why these self proteins are immunogenic in the first place. Our laboratory and office are located on the 10th floor of the Biomedical Science Tower of the University of Pittsburgh. The laboratory has 600 sq ft of space and is fully equipped for cellular immunology and molecular biology research and for all the projects described in this project. It is contiguous with other laboratories with the Department of Immunology and we have access to common use equipment and vast research support facilities. A pathogen-free animal facility run by the University is available in the same BST building and is AAALAC accredited.

Public Health Relevance

The studies described in this project, when completed, will provide an insight to the mechanism by which alpha2-macroglobulin elicits T cell immune responses and how this response can be harnessed to generate vaccines against cancer and infectious agents. These studies will provide preliminary data leading to clinical trials in cancer patients with autologous alpha2-macroglobulin-based vaccines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
5K22CA137133-03
Application #
8103864
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wali, Anil
Project Start
2009-07-02
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$160,023
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sedlacek, Abigail L; Kinner-Bibeau, Lauren B; Binder, Robert J (2016) Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity. Sci Rep 6:29889
Zhou, Yu Jerry; Messmer, Michelle Nicole; Binder, Robert Julian (2014) Establishment of tumor-associated immunity requires interaction of heat shock proteins with CD91. Cancer Immunol Res 2:217-28
Binder, Robert Julian (2014) Functions of heat shock proteins in pathways of the innate and adaptive immune system. J Immunol 193:5765-71
Messmer, Michelle Nicole; Pasmowitz, Joshua; Kropp, Laura Elizabeth et al. (2013) Identification of the cellular sentinels for native immunogenic heat shock proteins in vivo. J Immunol 191:4456-65
Pawaria, Sudesh; Kropp, Laura E; Binder, Robert J (2012) Immunotherapy of tumors with ?2-macroglobulin-antigen complexes pre-formed in vivo. PLoS One 7:e50365
Pawaria, Sudesh; Binder, Robert J (2011) CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun 2:521
Pawaria, Sudesh; Messmer, Michelle Nicole; Zhou, Yu Jerry et al. (2011) A role for the heat shock protein-CD91 axis in the initiation of immune responses to tumors. Immunol Res 50:255-60
Kropp, Laura E; Garg, Manish; Binder, Robert J (2010) Ovalbumin-derived precursor peptides are transferred sequentially from gp96 and calreticulin to MHC class I in the endoplasmic reticulum. J Immunol 184:5619-27