The Induction of Autoimmunity in Rabbits Following Injection of Heterologous or Altered Homologous Thyroglobulin

Weigle, William O.

doi:10.1084/jem.121.2.289

Cited by 106 publications

(46 citation statements)

References 13 publications

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“…Autoantibodies have been induced experimentally by other strategies. Immunization with foreign or modified selfantigens induces antibodies that cross-react with self antigens (38)(39)(40)(41)(42). Antiidiotypic antibodies that bind to self cell surface receptors can be produced by immunization with antibodies (idiotypes) directed against the receptor ligand (43-45).…”

Section: Discussionmentioning

confidence: 99%

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

Gharavi¹,

Sammaritano²,

Wen³

et al. 1992

J. Clin. Invest.

211

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A subset of patients with systemic lupus erythematosus has autoantibodies to acidic phospholipids. Since lipids are poor immunogens, the mechanism responsible for the induction of these antibodies is unclear. Immunization of a normal rabbit and normal mice with purified human g62-glycoprotein I (apolipoprotein H) resulted in the production of high levels of two non-cross-reactive antibody populations, anti-apolipoprotein H, and antiphospholipid. The antiphospholipid antibodies had binding specificities indistinguishable from autoantibodies obtained from human and murine lupus. These findings suggest a novel mechanism for the induction ofantiphospholipid autoantibodies. (J. Clin. Invest. 1992. 90:1105-1109

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Section: Discussionmentioning

confidence: 99%

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

Gharavi¹,

Sammaritano²,

Wen³

et al. 1992

J. Clin. Invest.

211

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“…A number of strategies are being pursued to address this challenge including the development of improved adjuvants, the introduction of foreign helper peptides into chimeric antigens, and the use of DNA vaccines (1)(2)(3)(4). Interestingly, almost 50 years ago, Weigle (5) showed that rabbits immunized with a rabbit thyroglobulin that had been nonspecifically labeled with a diazonium derivative produced cross-reactive antibodies to native thyroglobulin. Although these early experiments produced a highly heterogeneous antigen, one interpretation is that chemical modification results in immunogenic epitopes that induce high-titer crossreactive antibodies.…”

Section: Tnf-␣ ͉ Unnatural Amino Acids ͉ Vaccination ͉ Immunogenicitymentioning

confidence: 99%

Immunochemical termination of self-tolerance

Grünewald

Tsao

Perera

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The ability to selectively induce a strong immune response against self-proteins, or increase the immunogenicity of specific epitopes in foreign antigens, would have a significant impact on the production of vaccines for cancer, protein-misfolding diseases, and infectious diseases. Here, we show that site-specific incorporation of an immunogenic unnatural amino acid into a protein of interest produces high-titer antibodies that cross-react with WT protein. Specifically, mutation of a single tyrosine residue (Tyr 86 ) of murine tumor necrosis factor-␣ (mTNF-␣) to p-nitrophenylalanine (pNO2Phe) induced a hightiter antibody response in mice, whereas no significant antibody response was observed for a Tyr 86 3 Phe mutant. The antibodies generated against the pNO 2Phe are highly cross-reactive with native mTNF-␣ and protect mice against lipopolysaccharide (LPS)-induced death. This approach may provide a general method for inducing an antibody response to specific epitopes of self-and foreign antigens that lead to a neutralizing immune response.TNF-␣ ͉ unnatural amino acids ͉ vaccination ͉ immunogenicity

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“…Immunization with orthologs can overcome tolerance or ignorance to self antigens, including those expressed by cancer (9)(10)(11)(12)(13)(14)(15)(16)(17). This approach relies on small differences in amino acid sequences between orthologous proteins from mutations accumulated over tens of millions of years of evolution.…”

Section: Introductionmentioning

confidence: 99%

Optimization of a self antigen for presentation of multiple epitopes in cancer immunity

Guevara-Patiño¹

2006

Journal of Clinical Investigation

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T cells recognizing self antigens expressed by cancer cells are prevalent in the immune repertoire. However, activation of these autoreactive T cells is limited by weak signals that are incapable of fully priming naive T cells, creating a state of tolerance or ignorance. Even if T cell activation occurs, immunity can be further restricted by a dominant response directed at only a single epitope. Enhanced antigen presentation of multiple epitopes was investigated as a strategy to overcome these barriers. Specific point mutations that create altered peptide ligands were introduced into the gene encoding a nonimmunogenic tissue self antigen expressed by melanoma, tyrosinase-related protein-1 (Tyrp1). Deficient asparagine-linked glycosylation, which was caused by additional mutations, produced altered protein trafficking and fate that increased antigen processing. Immunization of mice with mutated Tyrp1 DNA elicited cross-reactive CD8 + T cell responses against multiple nonmutated epitopes of syngeneic Tyrp1 and against melanoma cells. These multispecific anti-Tyrp1 CD8 + T cell responses led to rejection of poorly immunogenic melanoma and prolonged survival when immunization was started after tumor challenge. These studies demonstrate how rationally designed DNA vaccines directed against self antigens for enhanced antigen processing and presentation reveal novel self epitopes and elicit multispecific T cell responses to nonimmunogenic, nonmutated self antigens, enhancing immunity against cancer self antigens. IntroductionT cells play a central role in immunity against cancer. Cancer antigens recognized by T cells are encoded by 2 broad categories of genes: those expressed by normal somatic and germ cells and those expressed only by cancer cells (e.g., due to mutations acquired during or after malignant transformation) (1, 2).A question had been whether T cells capable of recognizing self antigens on cancer cells are present in the repertoire. Evidence shows that T cells are positively selected for survival during development in the thymus by signals elicited by self peptides complexed with MHC molecules (pMHCs) and maintained in the periphery by self pMHCs (3-7). Thus the repertoire of T cells develops and is maintained through self reactivity. To avoid autoimmunity, T cells with high avidity for self pMHCs are deleted, but more weakly self-reactive T cells survive.This pool of T cells discriminates nonself antigens of pathogens by cross-reactivity to foreign peptides in the context of proinflammatory and costimulatory signals elicited by pathogens through activation of APCs. On the other hand, cognate self peptides are too weak to activate T cells, particularly in the absence of sufficient costimulation (8). A corollary to these observations is that, despite abundant self-reactive T cells in the peripheral immune system, initiation of T cell responses against self antigens on cancer are restricted by insufficient signals.

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The Induction of Autoimmunity in Rabbits Following Injection of Heterologous or Altered Homologous Thyroglobulin

Cited by 106 publications

References 13 publications

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

Immunochemical termination of self-tolerance

Optimization of a self antigen for presentation of multiple epitopes in cancer immunity

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