During the last decade it has been shown that some components of intravenous immunoglobulin (IVIG) are responsible for their broadly therapeutic application. Currently, such specific subfractions are defined as specific IVIG (sIVIG) and are affinity-purified from commercial IVIGs that target specific antigens/antibodies related to a specific autoimmune disease. A remarkable example of the therapeutic potential of sIVIG is the proven enhanced anti-inflammatory potency of sialylated and recombinant sialylated IVIG obtained from total IVIG. In other experimental models, it has also been demonstrated that sIVIG work in many other contrivances, such as revealing anti-idiotypic networks blocking pathogenic antibodies ameliorating disease activity. sIVIG has also been shown to exert its action by modulating specific receptors expressed on immune cells in both inflammatory and autoimmune diseases. Indeed, sIVIG has emerged as a novel approach to treat different immune-mediated conditions in a more accurate antigen-specific manner. Herein we review experimental evidence supporting sIVIG-efficacy in treating autoimmune diseases and inflammation.
Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (T RM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (T EM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+T RM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+T RM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+T RM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in T EM at the time of GvHD, possibly of donor derivation; (2) donor T RM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.
SummaryAdministration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anticitrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, lowdose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzymelinked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (T reg ) population by fluorescence activated cell sorter (FACS). ACPAsIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the T reg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the T reg population.
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