Cytokine-modulated dendritic cell immunotherapy in autoimmune diseases

• Autoimmunity is the result of failure of self-tolerance processes. When the immune system fails to differentiate self from foreign, the effector mechanisms are directed towards the individual s own tissues, and pathological autoimmune disease results. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that regulate immune responses. Mature DCs induce immunity that can be utilized in cancer treatment, whereas immature DCs induce tolerance, a property that can be utilized in the therapy of autoimmune diseases. The function of immature DCs can be further modified to suit the therapy of autoimmune diseases by exposing them to immunomodulatory cytokines. The aim of this thesis was to study the effects DCs exposed to the cytokines interleukin (IL)-10 (IL-10-DCs) and interferon (IFN)-gamma (IFN-gamma-DCs), respectively, in the treatment of myasthenia gravis (MG) and multiple sclerosis (MS), two autoimmune diseases with different immunological background. MG is a T cell dependent, antibody-mediated disease, while MS is mainly a T cell-mediated disease. Therefore, it is of interest to analyse the response to DC immunotherapy in both diseases. Paper I and IV revealed that IL-10-DCs and IFN-gamma-DCs, respectively, could efficiently suppress experimental autoimmune myasthenia gravis (EAMG) in Lewis rats, an animal model of MG. Rats with on-going EAMG developed less severe clinical signs when injected intraperitoneally with IL-10-DCs, or with IFN-gamma-DCs subcutaneously. Mononuclear cells (MNCs) from draining lymph nodes of rats treated with IL-10-DCs showed reduced proliferation, and reduced IL-10 and IFN-gamma production in response to nicotinic acetylcholine receptor (AChR). The proportion of AChR antibody-secreting cells among MNCs, and the affinity of the antibodies produced were reduced. The expression of CD80 and CD86 by MNCs was also reduced after treatment with IL-10-DCs. However, the treatment with IFN-gamma-DCs did not alter the proliferation of MNCs, nor the IL-10 or IFN-gamma production. There was a low number of AChR antibody-producing cells and plasma cells in rats treated with IFN-gamma-DCs, as well as a low number of B cell-activating factor (BAFF)-expressing cells. A specific inhibitor of indoleamine 2,3-dioxygenase (IDO), 1-methyl-DL-tryptophan (1-MT), aggravated the clinical signs of EAMG and abolished the IFN-gamma-DC-induced reduction in the number of AChR antibody-secreting cells in vitro. The results were suggestive of an 'IDO-BAFF pathway' in the suppression of EAMG by IFN-gamma-DCs. In Paper II and III, DCs generated from peripheral blood MNCs of patients with MG or MS, were modified in vitro with IL-10 or LPS, and co-cultured with autologous lymphocytes. DCs from healthy controls (HCs) were used for comparisons. Assessment of phenotype and cytokine secretion pattern of DCs revealed that irrespective of whether the DCs were generated from MG, MS or HCs, they responded to LPS, but not IL-10, with increased expression of HLA-DR, CD80, CD86 and CD83. Similarly, exposure of DCs to LPS, but not IL-10, increased secretion of the proinflammatory cytokines IL-12, IL-6 and TNF-alpha. IL-10-DCs were found to be resistant to maturation by LPS. In co-cultures, DCs derived from MG patients were more potent in activating T cells than DCs derived from HCs, as determined by the expression of CD25 and CD69 on CD4+ T cells. IL-10-DCs stimulated autologous lymphocytes to produce IL-10 and IL-4 in MS, MG and HCs. This was a Th2 response, indicating the possible benefit of IL-10-DCs in the treatment of MS, but not MG. Based on the present data and earlier data, IL-10-DCs and IFN-gamma-DCs appear as potential candidates for future clinical trials with DC immunotherapy in autoimmune diseases.

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