Abstract
Isologous and heterologous immunoglobulins have been shown to be extremely effective as tolerogenic carriers for nearly 30 years. The efficacy of these proteins is due in part to their long half-life in vivo, as well as their ability to crosslink surface IgM with Fc receptors. The concept of using IgG as a carrier molecule to induce unresponsiveness in the adult immune system has been exploited for simple haptens, such as nucleosides, as well as for peptides. To further evaluate the in vivo potential of these molecules for inducing tolerance to a defined epitope, we have engineered a fusion protein of mouse IgG1 with the immunodominant epitope 12-26 from bacteriophage λ cI repressor protein. This 15-mer, which contains both a B-cell and T-cell epitope, has been fused in-frame to the N terminus of a mouse heavy chain IgG1 construct, thus creating a 'genetic hapten-carrier' system. We describe a novel in vitro and in vivo experimental system for studying the feasibility of engineered tolerogens, consisting of a recombinant flagellin challenge antigen and a murine IgG1 tolerogen, both expressing the λ repressor epitope 12-26. Herein, we show that peptide-grafted IgG molecules injected i.v., or expressed by transfected, autologous B cells, can efficiently modulate the cellular and humoral immune responses to immunodominant epitopes. This model displays the feasibility of 'tailor-designing' immune responses to whole antigens by selecting epitopes for either tolerance or immunity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5019-5024 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 93 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 14 1996 |
| Externally published | Yes |
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Keywords
- antigen presentation
- gene therapy
- immune self-tolerance
- protein engineering
ASJC Scopus subject areas
- Genetics
- General
Cite this
Epitope-specific tolerance induction with an engineered immunoglobulin. / Zambidis, Elias; Scott, D. W.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 10, 14.05.1996, p. 5019-5024.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Epitope-specific tolerance induction with an engineered immunoglobulin
AU - Zambidis, Elias
AU - Scott, D. W.
PY - 1996/5/14
Y1 - 1996/5/14
N2 - Isologous and heterologous immunoglobulins have been shown to be extremely effective as tolerogenic carriers for nearly 30 years. The efficacy of these proteins is due in part to their long half-life in vivo, as well as their ability to crosslink surface IgM with Fc receptors. The concept of using IgG as a carrier molecule to induce unresponsiveness in the adult immune system has been exploited for simple haptens, such as nucleosides, as well as for peptides. To further evaluate the in vivo potential of these molecules for inducing tolerance to a defined epitope, we have engineered a fusion protein of mouse IgG1 with the immunodominant epitope 12-26 from bacteriophage λ cI repressor protein. This 15-mer, which contains both a B-cell and T-cell epitope, has been fused in-frame to the N terminus of a mouse heavy chain IgG1 construct, thus creating a 'genetic hapten-carrier' system. We describe a novel in vitro and in vivo experimental system for studying the feasibility of engineered tolerogens, consisting of a recombinant flagellin challenge antigen and a murine IgG1 tolerogen, both expressing the λ repressor epitope 12-26. Herein, we show that peptide-grafted IgG molecules injected i.v., or expressed by transfected, autologous B cells, can efficiently modulate the cellular and humoral immune responses to immunodominant epitopes. This model displays the feasibility of 'tailor-designing' immune responses to whole antigens by selecting epitopes for either tolerance or immunity.
AB - Isologous and heterologous immunoglobulins have been shown to be extremely effective as tolerogenic carriers for nearly 30 years. The efficacy of these proteins is due in part to their long half-life in vivo, as well as their ability to crosslink surface IgM with Fc receptors. The concept of using IgG as a carrier molecule to induce unresponsiveness in the adult immune system has been exploited for simple haptens, such as nucleosides, as well as for peptides. To further evaluate the in vivo potential of these molecules for inducing tolerance to a defined epitope, we have engineered a fusion protein of mouse IgG1 with the immunodominant epitope 12-26 from bacteriophage λ cI repressor protein. This 15-mer, which contains both a B-cell and T-cell epitope, has been fused in-frame to the N terminus of a mouse heavy chain IgG1 construct, thus creating a 'genetic hapten-carrier' system. We describe a novel in vitro and in vivo experimental system for studying the feasibility of engineered tolerogens, consisting of a recombinant flagellin challenge antigen and a murine IgG1 tolerogen, both expressing the λ repressor epitope 12-26. Herein, we show that peptide-grafted IgG molecules injected i.v., or expressed by transfected, autologous B cells, can efficiently modulate the cellular and humoral immune responses to immunodominant epitopes. This model displays the feasibility of 'tailor-designing' immune responses to whole antigens by selecting epitopes for either tolerance or immunity.
KW - antigen presentation
KW - gene therapy
KW - immune self-tolerance
KW - protein engineering
UR - http://www.scopus.com/inward/record.url?scp=0029995883&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029995883&partnerID=8YFLogxK
U2 - 10.1073/pnas.93.10.5019
DO - 10.1073/pnas.93.10.5019
M3 - Article
C2 - 8643522
AN - SCOPUS:0029995883
VL - 93
SP - 5019
EP - 5024
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 10
ER -