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Human ErbB-2 (Her-2) transgenic (Tg) mice were generated in C57BL/6 background (H-2b) to express Her-2 as a self-antigen. Vaccination of Her-2 Tg mice to overcome tolerance would mimic that in patients. Three-time electro-immunization with pE2TM encoding the extracellular and transmembrane domains of Her-2 together with pGM-CSF induced only moderate to poor α-Her-2 Ab response. Depletion of CD4+25+ regulatory T cells (Treg) with α-CD25 mAb before the 1st immunization increased the level of α-Her-2 Ab from 1.5 + 3.0 to 25 + 14 μg/ml. Increased T cell response was demonstrated by IFN-γ ELISPOT assay. The benefit of enhancing α-Her-2 immunity by Treg depletion may, however, be accompanied by an increased risk of autoimmunity to other self-antigens. In addition to Treg status, MHC II haplotypes are the major determinants of susceptibility to autoimmune diseases. In particular, expression of human HLA-DR3 predisposes humans to autoimmune thyroiditis and DR3 transgenic mice to experimental autoimmune thyroiditis (EAT). To assess the effect of Treg status on autoimmunity in high and low risk MHC background, Her-2 Tg (Her-2/IAb) mice were crossed with DR3/IAnull Tg mice to generate (Her-2/IAbxDR3)F1 mice. Immune reactivity to mouse thyroglobulin (mTg) was measured after 16 i.v. injections with 40 μg mTg over 4 wks or after two time i.v. injections with 40 μg mTg and 20 μg LPS with a 1 wk interval. Thyroid infiltration accompanied by destruction of the follicles was observed in Her-2/IAbxDR3 but not IAb mice that received mTg and LPS, showing that the additional DR3 transgene confers susceptibility to EAT. mTg specific Ab from Her-2/IAbxDR3 and Her-2/IAb mice which received 16X mTg injections were measured by ELISA. At 1:12,500, the level was 1.2 ± 0.6 and <0.2 (OD405), respectively. mTg specific T cell response measured by ELISPOT and T cell proliferation assays was significantly higher in Her-2/IAbxDR3 mice. Therefore, expression of DR3 resulted in strong immune reactivity to mTg. The effect of down-modulating Treg on concurrent Her-2 and mTg reactivity in Her-2/ IAbxDR3mice is being evaluated. Although Her-2/IAb mice are resistant to thyroiditis, depletion of Treg cells before the 1st mTg injection resulted in mTg Ab and IFN-γ producing T cells, comparable to those in Her-2/IAbxDR3 mice. These results demonstrate that the immune system of IAb or Her-2/IAb mice can respond to mTg, but this activity is suppressed by Treg. With reduced Treg, these mice become more susceptible to thyroiditis. In conclusion, when down-modulating Treg, the balance between the efficacy of cancer vaccine and the risk of autoimmunity may be influenced by MHC II haplotypes. It would be prudent to evaluate new cancer immunotherapy strategies accordingly. (CA76340, DOD W8IXWH-04-1-0546, DK45960, St. John’s Hospital and Medical Center).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]