In vivo induction of tolerance by an Ig peptide is not affected by the deletion of FcR or a mutated IgG Fc fragment.
To induce tolerance to a variety of epitopes, we have designed a gene therapy approach in which peptides or antigens are expressed in frame on a soluble IgG fusion protein scaffold and delivered via retroviral gene therapy in B cells in vivo. Initially, tolerance to the lambda repressor cI sequence p1-102 or its immunodominant epitopes (e.g. p12-26 or p73-88) was elicited in both T cells and B cells when lipopolysaccharide (LPS) blasts are transduced and injected into naive or even primed recipients. While a role of secreted Ig fusion protein in this process is not clear, we have previously demonstrated the importance of antigen presentation on MHC class II of B cell antigen-presenting cells (APC) for tolerance induction. To further examine the role of the Ig and especially of the Fc portion of the IgG in tolerogenesis, we transduced LPS blasts from FcR gamma II(-/-), Fc gamma RI(-/-), Fc gamma RIII(-/-), FcR(-/-) or naive mice with retroviral vectors expressing IgG1-102, Delta IgG1-102 (mutated construct on position 297 of the Fc portion) or IgG12-26. When these transduced LPS blasts from FcR knockout mice were injected into normal (or knockout) syngeneic recipient mice, they induced tolerance both to the immunodominant epitopes and the full-length protein in that the antibody responses to the immunodominant epitopes were reduced. In this paper, we show that this tolerance resides at both the T and B cell level. Moreover, mutation of residue 297, which affects IgG functions including FcR binding, did not alter the tolerogenicity of the construct. These results suggest that the Fc portion of the IgG molecules is not required for humoral nor for cellular tolerance induction using the IgG-antigen tolerogens.
el-Amine
Moustapha
M
Department of Immunology, American Red Cross, J. Holland Laboratory, Rockville, MD 20855, USA.
Hinshaw
Jennifer A
JA
Scott
David W
DW
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002455:Cell Division; D000939:Epitopes / Q000276:immunology; D005822:Genetic Vectors; D007108:Immune Tolerance; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009930:Organic Chemicals; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D009930:Organic Chemicals; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C029248:Tolerogen