Characterization of immunologic properties of a second HLA-A2 epitope from a granule protease in CML patients and HLA-A2 transgenic mice.

Abstract

The serine proteases, neutrophil elastase (HNE) and proteinase 3 (PR3), are aberrantly expressed in human myeloid leukemias. T-cell responses to these proteins have been correlated with remission in patients with chronic myeloid leukemia (CML). Human PR3/HNE-specific CD8(+) T cells predominantly recognize a nonameric HLA-A2-restricted T-cell epitope called PR1 which is conserved in both Ags. However, CML patients have CD8(+) T cells in peripheral blood recognizing an additional HLA-A2 epitope termed PR2. To assess immunologic properties of these Ags, novel recombinant vaccinia viruses (rVV) expressing PR3 and HNE were evaluated in HLA-A2 transgenic (Tg) mice (HHDII). Immunization of HHDII mice with rVV-PR3 elicited a robust PR3-specific CD8(+) T-cell response dominated by recognition of PR2, with minimal recognition of the PR1 epitope. This result was unexpected, because the PR2 peptide has been reported to bind poorly to HLA. To account for these findings, we proposed that HHDII mice negatively selected PR1-specific T cells because of the presence of this epitope within murine PR3 and HNE, leading to immunodominance of PR2-specific responses. PR2-specific splenocytes are cytotoxic to targets expressing naturally processed PR3, though PR1-specific splenocytes are not. We conclude that PR2 represents a functional T-cell epitope recognized in mice and human leukemia patients. These studies are registered at www.clinicaltrials.gov as NCT00716911.

• Authors: Simon F Lacey, Corinna La Rosa, Teodora Kaltcheva, Tumul Srivastava, Aprille Seidel, Wendi Zhou, Ravindra Rawal, Katharine Hagen, Aparna Krishnan, Jeff Longmate, Helen A Andersson, Lisa St John, Ravi Bhatia, Vinod Pullarkat, Stephen J Forman, Laurence J N Cooper, Jeffrey Molldrem, Don J Diamond
• Journal: Blood (Blood) Vol. 118 Issue 8 Pg. 2159-69 (Aug 25 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21719601 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• HLA-A2 Antigen
• Immunodominant Epitopes
• Recombinant Proteins
• Leukocyte Elastase
• Myeloblastin

Topics

• Amino Acid Sequence
• Animals
• Antigen Presentation
• CD8-Positive T-Lymphocytes (immunology)
• Cytoplasmic Granules (enzymology, immunology)
• Epitopes, T-Lymphocyte (genetics, immunology)
• HLA-A2 Antigen (genetics, immunology, metabolism)
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunodominant Epitopes (genetics, immunology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (immunology, therapy)
• Leukocyte Elastase (genetics, immunology)
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Myeloblastin (genetics, immunology)
• Recombinant Proteins (genetics, immunology)
• Sequence Homology, Amino Acid
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccinia virus (genetics, immunology)