A mouse model for immunotherapy of myeloma.

Abstract

Myeloma cells secrete monoclonal immunoglobulin (Ig), called myeloma protein. The variable (V) regions of myeloma proteins are unique to each plasma cell tumor, and therefore contain highly tumor-specific antigenic determinants called idiotopes (Id). In ongoing clinical trials, myeloma patients are vaccinated against the Id of their own myeloma protein. T cells with specificity for Id are thought to be of importance in eradication of multiple myeloma. We have developed a mouse model to study the molecular and cellular mechanisms for how Id-specific T cell protect against myeloma. A T cell receptor (TCR) transgenic mouse model has been established. CD4+ T cells in these mice recognize a particular Id-peptide presented on a MHC class II molecule. The Id-peptide represents an 11-mere of the variable region L chain of a particular mouse myeloma, MOPC315. TCR-transgenic mice are protected against a challenge with MOPC315 cells. Id-specific CD4+ cells protect in the absence of anti-Id antibodies. Dendritic cells in s.c. tumors take up myeloma protein and present Id-peptide on class II molecules to CD4+ cells which become activated and then kill bystander myeloma cells by an unknown mechanism. When TCR-transgenic mice are injected with large amounts of MOPC315 myeloma cells, resistance is overcome and some 30% of mice develop tumors. In these mice, Id-specific T cells become deleted as the myeloma protein serum concentration exceeds 50 microg/ml. In conclusion, in an experimental model, Id-specific CD4+ T cells protect against myeloma. However, once a tumor is established, Id-specific T cells become incapacitated. Based on these results, it is suggested that Id-vaccination in humans should be reserved for eradication of minimal residual disease, eg after high dose chemotherapy and stem cell transplantation.