|
Abstract
The specificity of immunogenicity of tumor-derived HSP preparations has been attributed to peptides chaperoned by HSPs. The following developments are to be discussed in this regard :
- A large number of peptides associated naturally with hsp70 have recently been isolated and sequenced (1).
- A large number of peptides associated naturally with gp96 have also been isolated and sequenced (2, unpublished, and to be presented at the meeting). Evidence of peptide chaperoning by an HSP in a prokaryotic system shall be presented (3).
- The peptide-binding domain of hsp70 has been long characterized (4), and a similar domain for gp96 has recently been characterized (5).
- The idea that the immunogenicity of tumor-derived gp96 preparations is non-specific, has been raised recently (6). This idea has been refuted by several lines of evidence including #3 above.
- The uptake of gp96 (and other HSPs) has been shown to be mediated through CD91 molecule on the APCs (7, 8). Evidence against this observation was recently published (9). The lacunae in that evidence have been pointed out and published recently (10).
- The role of CD91 and LOX1 in presentation of gp96-chaperoned peptides by MHC II shall be presented (11).
- Data regarding an essential physiological role of HSP-peptide complexes in cross-priming shall be discussed (12, 13).
- Clinical data on the use of gp96-peptide complexes for immunotherapy of human cancer shall be presented.
|
|
 |
References
1. Grossmann ME, Madden BJ, Gao F, Pang YP, Carpenter JE, McCormick D, Young CY. Proteomics shows Hsp70 does not bind peptide sequences indiscriminately in vivo. Exp Cell Res 2004; 297: 108-17. (PMID: 15194429)
2. Liu et al. Structural analysis of gp96-associated peptides: consequences for immunogenicity. Manuscript in preparation.
3. Kelly et al. See poster at this meeting.
4. Zhu X, Zhao X, Burkholder WF, Gragerov A, Ogata CM, Gottesman ME, Hendrickson WA. Structural analysis of substrate binding by the molecular chaperone DnaK. Science 1996; 272: 1606-14. (PMID: 8658133)
5. Gidalevitz T, Biswas C, Ding H, Schneidman-Duhovny D, Wolfson HJ, Stevens F, Radford S, Argon Y. Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J Biol Chem 2004; 279: 16543-52. (PMID: 14754890)
6. Baker-LePain JC, Sarzotti M, Fields TA, Li CY, Nicchitta CV. GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression. J Exp Med 2002; 196: 1447-59. (PMID: 12461080)
7. Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nat Immunol 2000; 1: 151-5. (PMID: 11248808)
8. Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 2001; 14: 303-13. (PMID: 11290339)
9. Berwin B, Hart JP, Pizzo SV, Nicchitta CV. CD91-independent cross-presentation of GRP94(gp96)-associated peptides. J Immunol 2002; 168: 4282-6. (PMID: 11970968)
10. Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci U S A 2004; 101: 6128-33. (PMID: 15073331)
11. Matsutake and Srivastava. See poster at this meeting.
12. Binder and Srivastava. See poster at this meeting.
13. Callahan et al. See poster at this meeting.
|
