Abstracts of 4^th Annual UKMF Scientific Meeting on 07-Feb-2003

Idiotype-specific T cells in multiple myeloma

Bjarne Bogen, Institute of Immunology, University of Oslo, Rikshospitalet, 0027 Oslo, Norway.

Background: CD4⁺ T cells are believed to play a key role in antitumor immunity. We have studied the role of Idiotype(Id)-specific CD4⁺ T cells in multiple myeloma. To this end we have developed a TCR-transgenic mouse model in which CD4⁺ T cells recognize an Id-peptide corresponding to residues 91-101 of the λ2³¹⁵ L-chain of myeloma protein M315 (αλ2) produced by the class II negative MOPC315 plasmacytoma. The Id-petide is presented by the MHC class II molecule I-E^d. TCR-transgenic mice have been shown to be resistant to a s.c. challenge with MOPC315 [PNAS 94, Eur. J. Immunol 95]. The resistance is partially overcome when TCR transgenic mice are injected with high loads of MOPC315 cells. As plasmacytoma growth progresses, high dose-injected TCR transgenic mice delete Id-specific thymocytes [Int. J. Cancer 98] and peripheral CD4⁺ T cells [Eur. J. Immunol 96]. It is difficult to study the mechanism by which Id-specific CD4⁺ T cells kill myeloma cells in vivo because there is no tumor specimen to study. We have therefore resorted to study immunological reactions taking place in small MOPC315 tumors in high dose-injected TCR-transgenic mice, prior to T cell tolerance development. We have demonstrated that professional APC in MOPC315 tumors are primed with Id and are able to stimulate Id-specific CD4⁺ cells. The APC have dendrites, phagocytose, and are class II⁺, CD86⁺, CD11b⁺, CD11c⁺, thus resembling immature dendritic cells. Furthermore, small MOPC315 tumors contain activated (CD69⁺CD25⁺) transgenic Id-specific CD4⁺ blasts which incorporate BrdU in vivo and have a memory phenotype (CD44⁺CD45RB⁺CD62L⁺) [PNAS 2000, Blood 2001].

Present work: (i) To study the very initial influx of host cells into the s.c. MOPC315 tumors, we have used tumor cells suspended in Matrigel. As early as day 3 after injection, we see a massive influx of CD11b⁺ macrophage/immature DC-like cells. These may correspond to the class II⁺, CD86⁺, CD11b⁺, CD11c⁺ cells described in established tumors (see above). Id-specific T cells are scarce at these early timepoints. (ii) We have studied the requirement of secretion of myeloma protein to obtain tumor protection in TCR-transgenic mice. For this purpose, a variant (MOC315.37) that retains the λ2³¹⁵ L-chain intracellularly was employed. TCR-transgenic mice were not protected against MOC315.37, suggesting that secretion of myeloma protein is required to prime APC for induction of tumorprotective Id-specific CD4⁺ responses. (iii) It may be argued that s.c. injection of tumor cells is a poor model for multiple myeloma where cells primarily grow in the bone marrow. We therefore selected a MOPC315 variant that readily induced disease in bone marrow, liver and spleen upon i.v. injection. TCR-transgenic mice were protected against this highly malignant variant suggesting that Id-specific T cells exert their protective effect not only in a s.c. site but also in other places like in the bone marrow.

Conclusion: Id-specific CD4⁺ cells become activated by Id-primed professional APC that pick up secreted myeloma protein. Activated Id-specific CD4⁺ cells kill myeloma cells by an unknown mechanism. If Id-specific CD4⁺ cells fail to kill the myeloma cells, they will themselves become deleted and myeloma growth progresses.

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