Deregulated cytokine network and defective Th1 immune response in multiple myeloma

Abstract

SUMMARYIntracellular cytokine production by peripheral blood mononuclear cells (PBMC) was analysed in 51 patients with multiple myeloma (MM), 22 with monoclonal gammopathy of undetermined significance (MGUS) and 20 healthy subjects, as a parameter of immunological dysfunction in MM. An increased proportion of T cells and HLA-DR 1 cells producing IL-6 was observed in MM patients with active disease (at diagnosis and relapsing) compared with patients in remission and with MGUS, whereas no difference of IFN-g 1 , IL-2 1 PBMC between patients and controls was evident. Determination of serum cytokine levels demonstrated that the imbalanced IL-6 production by T cells and the defective antitumour Th1 cell activity were related to elevated levels of IL-6 and IL-12. In vitro studies of PHA-and anti-CD3/anti-CD28 MoAbs stimulation of PBMC demonstrated the ability of lymphocytes from MM patients to differentiate towards the Th1 subset in the presence of rIL-12. By contrast, addition of exogenous rIL-6 impaired IFN-g production by rIL-12-prompted T cells. Inhibition of Th1 polarization of the immune response by IL-6 was direct on T cells and not mediated by dendritic cells (DC). Evaluation of the ability of MM-derived DC to stimulate cell proliferation of allogenic T lymphocytes and produce IL-12 in vitro, in fact, suggested that MM-derived DC were functionally active. Taken as a whole, these results indicate that a deregulated cytokine network occurs in active MM. They also suggest that increased IL-6 production by peripheral T lymphocytes contributes to the immune dysfunction observed in MM, and enables tumour cells to escape immune surveillance by preventing the anti-tumour Th1 immune response.

Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease

“…27 In agreement with all these observations a defective IFN-␥ secretion by T cells was observed in MM patients. 28 The decrease in IFN-␥ levels observed in our cocultures could be due to the production of immunosuppressive factors by myeloma cells such as transforming growth factor ␤ (TGF-␤). It has been demonstrated that TGF-␤ from MM cells inhibits proliferation and IL-2 responsiveness in T lymphocytes, 29 and it is known that TGF-␤ suppresses IFN-␥ production in human T lymphocytes.…”

Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy

“…34,35 This cytokine counterbalances the Th-2 polarizing activity of GM-CSF and restores the intrinsically defective Th-1 cytokine network of MM patients. 36 The TCR repertoire is determined by genetic and environmental factors, and is dynamically influenced by immune responses. Determination of the clonality and reciprocal usage of BV gene segments has shown that the TCR repertoire is severely disrupted in MM patients after high-dose chemotherapy and PBPC infusion.…”

Association of Antigen-Specific T-cell Responses with Antigen Expression and Immunoparalysis in Multiple Myeloma

“…The corresponding myelomatous bone marrow is significantly altered due to factors aberrantly expressed by myeloma cells, those that are already expressed by normal plasma cells but present in higher abundance, and such expressed by a variety of cells of the (changing) bone marrow microenvironment (6)(7)(8)(10)(11)(12). One of the most prominent effects, thereof, is the induction of immunosuppression (13) visible in dysfunctional dendritic cells (DC) and diminished T-cell activation (13,14).…”