Anti-idiotypic immunity against AB cell lymphoma

George, Andrew John Timothy (1987) Anti-idiotypic immunity against AB cell lymphoma. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The idiotypic determinants carried on the surface immunoglobulin molecules of B cell tumours can function as highly specific tumour associated antigens. In this study I have shown that immunisation of BALB/c mice with idiotypic IgM derived from the syngeneic lymphoma BCL₁ can specifically protect the animals from subsequent challenge with BCL₁ tumour, with 70/90 immunised mice surviving > 100 days post challenge, compared to control animals which survived a mean of 40 days. In addition the immunisation of mice, which had been previously inoculated with BCL₁ tumour, with BCL₁ IgM conjugated to keyhole limpet hemacyanin proved effective in the treatment of established disease. Both idiotype specific T cells and cytotoxic antibody have been demonstrated to be induced by immunisation. Passive transfer experiments have suggested that idiotype specific antibody may be implicated in the protection, and no role for the immune cells could be demonstrated. However the levels of anti-idiotypic antibody seen in immunised animals did not correlate with the survival seen following challenge with BCL₁. Tumour cells inoculated into immunised animals were not completely eradicated, but could remain in a dormant state in the spleen of the animals for long periods of time (> 6 months). The presence of such dormant tumour cells was demonstrated by immunohistological techniques and the emergence of tumour in the recipients of spleen cells from apparently healthy long term survivors. Escape of the tumour from the dormant state was associated with a population of cells that neither expressed idiotypic IgM on their surface, nor secreted it in vivo or in vitro. The cells did, however, contain idiotypic material in their cytoplasm. A stable variant of the BCL₁ tumour, SNAG 1, was isolated with this phenotype. In initial experiments to determine the genetic lesion underlying the altered phenotype of SNAG 1 cells no difference between the molecular weight of the IgM heavy and light chains could be demonstrated. The SNAG 1 tumour also has a different pattern of growth from BCL₁; it takes longer to grow and kill the animals and it shows a relatively greater liver involvement than BCL₁. It also fails to respond to lipopolysaccharide by either proliferation or secretion of idiotypic IgM. This variant, therefore, not only documents a novel mechanism whereby tumour cells can escape from an anti-idiotype immune response, but may also prove a valuable tool in determining the role of surface immunoglobulin in cell migration and response to growth factors. The use of idiotypic vaccination may prove useful in the therapy of human lymphoma. The emergence of variants similar to SNAG 1 may prove an obstacle to the success of such an approach, but the slow growth of SNAG 1 suggests that such immunoselected variants may have a more benign course.

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