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Immunosuppressory mini-regions of HLA-DP and HLA-DR
Z Szewczuk1, A Wilczyński, P Stefanowicz
1Faculty of Chemistry, University of Wroclaw, Poland. scewczuk@wchuwr.chem.uni.wroc.pl
Abstract:
Our previous studies showed, that the,TPQRGDVYT, QRGDVYT and RGDVYT fragments, located in the beta164-172 loop of HLA-DQ, strongly suppress the humoral and cellular immune response, while their shorter analogs, RGDV, RGDVY, and QRGDVY, show only weak stimulatory activity in respect to humoral immunological response. The fragments contain the RGDVY sequence that is analogous to thymopentin (pentapeptide RKDVY, an immune system activator) as well as the RGD sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog C*RGDVYC* (where C* indicates Cys participating in disulfide bridge) with restricted conformation, which strongly suppresses both humoral and cellular immune response. In the present study we synthesized and tested the immunological properties of the linear and cyclic HLA-DP and HLA-DR counterparts of all the above HLA-DQ fragments. Although the results show that the linear HLA-DP fragments possess moderate immunosuppressory potency, their conformationally restricted analog, C*QGDVYC*C shows a considerable suppression of both humoral and cellular immune response. The nonapeptide fragment of HLA-DR, VPRSGEVYT and particularly its cyclic analog C*SGEVYC*, are strong suppressors of the humoral response.
Insights
Fragments from HLA-DQ, DP, and DR molecules were synthesized and tested. Cyclic analogs of HLA-DP and HLA-DR fragments demonstrated significant immunosuppressive properties, impacting both humoral and cellular immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Previous studies identified specific HLA-DQ fragments (TPQRGDVYT, QRGDVYT, RGDVYT) that strongly suppress immune responses.
- These fragments contain RGDVYT sequences, similar to thymopentin, and RGD sequences crucial for cell association.
- A cyclic analog of an HLA-DQ fragment (C*RGDVYC*) with restricted conformation showed potent immunosuppression.
Purpose of the Study:
- To synthesize and evaluate the immunological properties of linear and cyclic HLA-DP and HLA-DR fragments.
- To compare the immunosuppressive potential of these fragments with previously studied HLA-DQ analogs.
- To investigate the role of conformational restriction in the immune modulatory activity of these peptides.
Main Methods:
- Synthesis of linear and cyclic peptide fragments derived from HLA-DP and HLA-DR molecules.
- Testing of synthesized fragments for their effects on humoral and cellular immune responses.
- Utilizing knowledge of HLA-DR1 crystal structure for designing cyclic analogs.
Main Results:
- Linear HLA-DP fragments exhibited moderate immunosuppressive potency.
- A cyclic analog of an HLA-DP fragment (C*QGDVYC*C) demonstrated considerable suppression of both humoral and cellular immune responses.
- A nonapeptide fragment of HLA-DR (VPRSGEVYT) and its cyclic analog (C*SGEVYC*) were identified as strong suppressors of the humoral response.
Conclusions:
- Conformationally restricted cyclic analogs of HLA-DP and HLA-DR fragments possess significant immunosuppressive capabilities.
- These findings expand on previous work with HLA-DQ fragments, highlighting the potential of specific peptide sequences and structures in modulating immune activity.
- The study suggests that HLA-DP and HLA-DR derived peptides, particularly cyclic forms, can be potent modulators of immune responses.