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Coupling and uncoupling of tumor immunity and autoimmunity.

Bowne WB, Srinivasan R, Wolchok JD, Hawkins WG, Blachere NE, Dyall R, Lewis JJ, Houghton AN - J. Exp. Med. (1999)

Bottom Line: Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin.Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell.However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

ABSTRACT
Self-antigens, in the form of differentiation antigens, are commonly recognized by the immune system on melanoma and other cancers. We have shown previously that active immunization of mice against the melanocyte differentiation antigen, a tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locus protein) expressed by melanomas, could induce tumor immunity and autoimmunity manifested as depigmentation. In this system, tumor immunity and autoimmunity were mediated by autoantibodies. Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization. As observed previously for gp75(TRP-1), immunity was induced by DNA immunization against a xenogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2 induced autoantibodies and autoreactive cytotoxic T cells. In contrast to immunization against gp75(TRP-1), both tumor immunity and autoimmunity required CD8(+) T cells, but not antibodies. Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin. Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.

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Related in: MedlinePlus

CTL response to TRP-2181–188 peptide in mice that were not immunized (A), or immunized with mTRP-2 (B) or hTRP-2 (C). C57BL/6 mice (2 or 3 per group) were immunized as described in the legend to Fig. 1. 7 d after the last immunization, draining lymph nodes were pooled and stimulated as described in Materials and Methods for 5 d and tested for cytotoxicity against EL-4 target cells, either pulsed with TRP-2 peptide or unpulsed. Results are representative of two experiments.
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Figure 2: CTL response to TRP-2181–188 peptide in mice that were not immunized (A), or immunized with mTRP-2 (B) or hTRP-2 (C). C57BL/6 mice (2 or 3 per group) were immunized as described in the legend to Fig. 1. 7 d after the last immunization, draining lymph nodes were pooled and stimulated as described in Materials and Methods for 5 d and tested for cytotoxicity against EL-4 target cells, either pulsed with TRP-2 peptide or unpulsed. Results are representative of two experiments.

Mentions: CTL responses against TRP-2 were detected after immunization with xenogeneic hTRP-2, but not syngeneic mTRP-2 DNA. Specifically, CD8+ CTL from draining lymph nodes (supraclavicular nodes), stimulated in vitro for 5 d, recognized an MHC class I H-2Kb–restricted peptide of mTRP-2 after immunization with hTRP-2 DNA (Fig. 2 [9]). Interestingly, the H-2Kb–restricted peptide of mTRP-2, mTRP-2181–188, is identical between mouse and human TRP-2, including the immediate flanking amino acid residues. Thus, this self-peptide in the context of self–TRP-2 DNA does not induce CTL responses, but presentation of the same peptide in the context of xenogeneic hTRP-2 is immunogenic.


Coupling and uncoupling of tumor immunity and autoimmunity.

Bowne WB, Srinivasan R, Wolchok JD, Hawkins WG, Blachere NE, Dyall R, Lewis JJ, Houghton AN - J. Exp. Med. (1999)

CTL response to TRP-2181–188 peptide in mice that were not immunized (A), or immunized with mTRP-2 (B) or hTRP-2 (C). C57BL/6 mice (2 or 3 per group) were immunized as described in the legend to Fig. 1. 7 d after the last immunization, draining lymph nodes were pooled and stimulated as described in Materials and Methods for 5 d and tested for cytotoxicity against EL-4 target cells, either pulsed with TRP-2 peptide or unpulsed. Results are representative of two experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195744&req=5

Figure 2: CTL response to TRP-2181–188 peptide in mice that were not immunized (A), or immunized with mTRP-2 (B) or hTRP-2 (C). C57BL/6 mice (2 or 3 per group) were immunized as described in the legend to Fig. 1. 7 d after the last immunization, draining lymph nodes were pooled and stimulated as described in Materials and Methods for 5 d and tested for cytotoxicity against EL-4 target cells, either pulsed with TRP-2 peptide or unpulsed. Results are representative of two experiments.
Mentions: CTL responses against TRP-2 were detected after immunization with xenogeneic hTRP-2, but not syngeneic mTRP-2 DNA. Specifically, CD8+ CTL from draining lymph nodes (supraclavicular nodes), stimulated in vitro for 5 d, recognized an MHC class I H-2Kb–restricted peptide of mTRP-2 after immunization with hTRP-2 DNA (Fig. 2 [9]). Interestingly, the H-2Kb–restricted peptide of mTRP-2, mTRP-2181–188, is identical between mouse and human TRP-2, including the immediate flanking amino acid residues. Thus, this self-peptide in the context of self–TRP-2 DNA does not induce CTL responses, but presentation of the same peptide in the context of xenogeneic hTRP-2 is immunogenic.

Bottom Line: Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin.Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell.However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

ABSTRACT
Self-antigens, in the form of differentiation antigens, are commonly recognized by the immune system on melanoma and other cancers. We have shown previously that active immunization of mice against the melanocyte differentiation antigen, a tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locus protein) expressed by melanomas, could induce tumor immunity and autoimmunity manifested as depigmentation. In this system, tumor immunity and autoimmunity were mediated by autoantibodies. Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization. As observed previously for gp75(TRP-1), immunity was induced by DNA immunization against a xenogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2 induced autoantibodies and autoreactive cytotoxic T cells. In contrast to immunization against gp75(TRP-1), both tumor immunity and autoimmunity required CD8(+) T cells, but not antibodies. Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin. Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.

Show MeSH
Related in: MedlinePlus