Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells.
Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with, Her-2xDR3 and B6xDR3 mice expressing H2(b)xDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2(b) haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles.
Jacob
Jennifer B
JB
Karmanos Cancer Institute, Department of Immunology and Microbiology, School of Medicine, Wayne State University, 101 East Warren Avenue, Detroit, MI 48201, USA.
Kong
Yi-chi M
YC
Meroueh
Chady
C
Snower
Daniel P
DP
David
Chella S
CS
Ho
Ye-Shih
YS
Wei
Wei-Zen
WZ
D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D019496:Cancer Vaccines / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000737:chemistry; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013961:Thyroid Gland / Q000276:immunology*
D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases