title: Immunoglobulin light chain, Blimp-1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis.
abstract: Amyloid light chain (AL) amyloidosis is a lethal disorder characterized by the pathologic deposition of clonal plasma cell-derived, fibrillogenic immunoglobulin light chains in vital organs. Current chemotherapeutic regimens are problematic in patients with compromised organ function and are not effective for all patients. Here, a platform of computer-based prediction and preclinical mouse modeling was used to begin development of a complementary, immunotherapeutic approach for AL amyloidosis. Three peptide/MHC I-binding algorithms identified immunogenic peptides from three AL plasma cell-associated proteins: (1) amyloidogenic λ6 light chains, (2) CYP1B1, a universal tumor antigen hyper-expressed in AL plasma cells and (3) B lymphocyte-induced maturation protein 1 (Blimp-1), a transcription factor required for plasma cell differentiation. The algorithms correctly predicted HLA-A(*)0201-binding native and heteroclitic peptides. In HLA-A2 transgenic mice, these peptides, given individually or in combination, induced potent CTL which kill peptide-loaded human lymphoma cells and/or lymphoma cells producing target protein. Blimp-1 peptide-immunized mice exhibited a reduced percentage of splenic, lymph node and bone marrow plasma cells and a decrease in the absolute number of splenic plasma cells demonstrating (1) presentation of target peptide by endogenous plasma cells and (2) appropriate CTL homing to lymphoid organs followed by killing of target plasma cells. These studies suggest that AL amyloidosis, with its relatively low tumor cell burden, may be an attractive target for peptide-based multivalent vaccines.
authors: Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Amanda
authors: A
authors: Flies
authors: Tahamtan
authors: T
authors: Ahmadi
authors: Ashley J
authors: AJ
authors: Parks
authors: Tatiana
authors: T
authors: Prokaeva
authors: Liangping
authors: L
authors: Weng
authors: Sandra Solomon
authors: SS
authors: Rolfe
authors: David C
authors: DC
authors: Seldin
authors: David H
authors: DH
authors: Sherr
mesh_terms: D000682:Amyloid / Q000276:immunology*; D000686:Amyloidosis / Q000276:immunology* / Q000628:therapy*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002465:Cell Movement; D019295:Computational Biology; D065633:Cytochrome P-450 CYP1B1; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000682:Amyloid; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007147:Immunoglobulin Light Chains; D010446:Peptide Fragments; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D022223:Vaccines, Subunit; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D000074462:Positive Regulatory Domain I-Binding Factor 1