Anti-idiotypic immunity in multiple myeloma and monoclonal gammopathy of undetermined significance

University dissertation from Stockholm : Karolinska Institutet, false

Abstract: Monoclonal gammopathies such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are lymphoproliferative B cell diseases. B cells/plasma cells produce the monoclonal immunoglobulin (Ig) which can be detected in plasma and/or urine. Such Ig have unique variable regions of the heavy and light chains and may be regarded as tumour-specific antigens and as such potential targets for immune regulation of the tumour cell clone, by anti-idiotype (Id) immune reactions. The production of anti-Id Ab against the M-component by primary B cell lines of Epstein-Barr virus transformed PBMC was analysed in patients with MM and MGUS. Patients with advanced disease (MM stage III) had a low and patients with MM stage I and MGUS a high production of such anti-ld Ab (p<0.0 1). Anti-Id B cells were studied in patients with MM, MGUS and in healthy controls using an ELISPOT assay. All patients had B cells producing Ab to F(ab+)2 fragments of autologous and allogeneic M-components. There was no difference between patients with MM and MGUS with regard to the number of B cells producing Ab against autologous M-component. MGUS and MM patients had autoreactive B cells more frequently than alloreactive B cells (p<0.00 1). The number of alloreactive B cells did not differ between patients and controls. T cells reactive with F(ab+)2 fragments of autologous and allogeneic M-components were analysed in patients with MM, MGUS and in healthy controls using an ELISPOT assay. In patients, the number of T cells that were stimulated by autologous M-component was higher (p<0.01), than the number of cells activated by allogeneic Ig. Subpopulations of Id-reactive T cells were defined by demonstrating Th cells with different cytokine-secreting patterns after stimulation by F(ab+)2 fragments of autologous M-components using ELISPOT assays. ThI -type cells (secreting IFN-y and IL-2) were more frequent in patients with a low tumour burden. Th2-type cells (secreting IL-4) dominated in patients with MM stage II-III. The T cell response was MHC class II-restricted. Id-reactive T cells were also demonstrated in MM and MGUS patients with 3H-thymidine-incorporation. The proliferation of cells was higher when stimulating PBMC with F(ab+ )2 fragments of autologous M-component (p<0.05) than with allogeneic M-components. Injection of autologous M-component suspended in alum into five MM patients induced an in vitro Id-specific response in both T and B cells. The response was reduced during repeated immunisations. In conclusion, the results indicate a presence of immunity against Id determinants on monoclonal Ig. Ab, B and T cells with reactivity against F(ab+)2 fragments of autologous M-components exist in both MM and MGUS. Their presence in these disorders may indicate a regulatory function. These findings form a basis for further studies aiming at identifying new ways to enhance a specific anti-tumour response in MM.

  This dissertation MIGHT be available in PDF-format. Check this page to see if it is available for download.