Namita Misra

Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over two decades. Since the early 1980s, the therapeutic efficacy of IVIg has been established in idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki syndrome, and the prevention of graft versus host disease in recipients of allogeneic bone marrow transplants. Its use has also been reported in a large number of other autoimmune and systemic inflammatory conditions. In this review, we discuss the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.

Reduced Immunoregulatory CD31 + T Cells in Patients With Atherosclerotic Abdominal Aortic Aneurysm

Background—Cell-mediated immunity is considered to contribute to the pathogenesis of abdominal aortic aneurysms (AAA). In particular, infiltrating macrophages and CD8+ T lymphocytes participate in the destruction of the aortic wall extracellular matrix and smooth muscle cells. We surmise that these pathological events are controlled by circulating regulatory lymphocytes. Methods and Results—Circulating CD4+/CD31+ cells were reduced in AAA patients (n=80, 8.9±0.6%) as compared with controls (n=69, 13.7±0.8%; P<0.001) and inversely proportional to AAA size. Exclusion of the aneurysm by an endoprothesis did not affect CD31+ T cell values. Reduction of blood CD4+/CD31+ cells was not attributable to their enrichment in AAA tissue. In contrast, CD8+/CD31+ cells were slightly reduced in the blood while increased in the aneurysmal tissue (29.2±0.5 versus 20.2±4.7% in blood, n=6; P<0.05). Remarkably, high percentages of CD4+/CD31+ cells were able to regulate proliferation and cytokine production of CD8+ lymphocytes, as well as CD8+ cell-mediated cytotoxicity of aortic smooth muscle cells (P<0.01). Finally, CD4+/CD31+ cells reduced the production and activity of metalloproteinase-9 by lipopolysaccharide-stimulated macrophages. Conclusions—Circulating CD4+/CD31+ T cells regulate macrophage and CD8+ T cell activation and effector function in the arterial wall. Their reduction might promote the development of AAA.

Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases

Abstract.Intravenous immunoglobulins (IVIg) exert a broad range of immunoregularoty functions that provide a basis for the beneficial effects of IVIg in autoimmune and systemic inflammatory disorders. This review focuses on the effects f IVIg on humoral and cellular inmmunity that may be of relevance for the treatment of inflammatory neurological diseases.

Dendritic cells and autoimmunity

Dendritic cells (DC) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Because of their capacity to stimulate naive T cells, DC have a central role in the initiation of primary immune responses and are considered promising tools and targets for immunotherapy. Emerging data suggest a role for DC in initiating autoimmune attacks. Direct analysis of DC phenotypes and DC-T-cell interactions in rodent and human autoimmune diseases should shed light on how pathogenesis occurs, and suggest novel avenues of treatment aimed at alleviating deviant DC function.

Intravenous immunoglobulin in neurological disorders: a mechanistic perspective.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP),myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions.

Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

In the present study, we have analyzed the T cell receptor (TCR) repertoires of CD4+ T cells isolated from peripheral blood of 10 inhibitor-positive patients with severe hemophilia A. The distribution of complementarity determining region (CDR3) lengths of the beta chain of the TCRs was analyzed by spectratyping prior to and following in vitro stimulation of the cells with human factor VIII (FVIII). The repertoires of CD4+ T cells of patients were perturbed when compared to those of healthy blood donors. The perturbations of T cell repertoires were heterogeneous among patients with respect to the number and the nature of V-beta (BV) families that exhibited expansion following incubation with FVIII. Some patients showed alterations in one or two BV families, others exhibited more perturbed repertoires affecting 5 to 8 of the 14 BV families tested. Alterations of BV2, BV5 and/or BV9 were consistently found after incubation of CD4+ T cells in the presence of FVIII in 80% of the patients. These findings indicate that the presence of FVIII inhibitors in patients with severe hemophilia A is associated with measurable perturbations of the CD4+ T cell repertoire that results from oligoclonal expansion of FVIII-specific cells and may be relevant for the design of strategies aimed at modulating the anti-FVIII immune responses by T cell-targeted therapy

Immunoglobulin-Dependent Regulation of Dendritic Cells in the Context of Autoimmune Responses

Dendritic cells (DC) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Because of their capacity to stimulate naïve T cells, DC have a central role in the initiation of primary immune responses and are considered promising tools and targets for immunotherapy. Investigating the signals that regulate the function of DC, the sentinels of the immune system, is also critical to understanding the role of DC in the regulation of immune response. We have assessed the effects of natural antibodies in the form of therapeutic intravenous immunoglobulins (IVIg) on the regulation of the function of DC. We have observed that DC are the primary targets for the immunosuppressive effects of IVIg on T-cell activation. This review focuses on the effects of IVIg on DC development and function.

The concept of idiotypic vaccination against factor VIII inhibitors in haemophilia A.

Summary.  Idiotypic vaccination has proven successful in several animal models and human trials. Here we suggest that the expression of cross‐reactive idiotypes on factor VIII (FVIII) inhibitors of patients with haemophilia A, patients with anti‐FVIII autoimmune disease and natural anti‐FVIII antibodies of healthy individuals, together with the ability of anti‐idiotypic reagents to neutralize anti‐FVIII antibodies, provides a rationale for designing a vaccine strategy aimed at preventing the occurrence of or suppressing inhibitors, based on the induction of protective anti‐idiotypes. Here we discuss the rationale supporting the concept of using idiotypic vaccination to prevent the occurrence of FVIII inhibitors in patients with haemophilia A.