Amir Hossein Massoud

Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3–positive regulatory T cells

BACKGROUND Intravenous immunoglobulin (IVIG) is a frequently used disease-modifying therapy for a large spectrum of autoimmune and inflammatory conditions, yet its mechanisms of action are incompletely understood. Using a robust murine model of antigen-driven allergic airways disease, we have demonstrated that IVIG markedly improves ovalbumin (OVA)-induced airway hyperresponsiveness characterized by 4- to 6-fold enhancement in regulatory T (Treg) cells in pulmonary and associated lymphoid tissues. OBJECTIVE We sought to determine whether IVIG induces antigen-specific Treg cells and to address cellular interactions that lead to induction of Treg cells by IVIG. METHODS C57Bl/6 mice were sensitized and challenged by means of intranasal OVA exposure. IVIG or albumin control was administered 24 hours before challenge. Treg cells were tracked by using green fluorescent protein (GFP)-forkhead box protein 3 (Foxp3) knock-in reporter mice (Foxp3(GFP)), and Treg cell and dendritic cell (DC) phenotypes and activities were elucidated by using coculture and flow cytometry. RESULTS IVIG therapy of OVA-sensitized and OVA-challenged mice induced antigen-specific forkhead box protein 3 (Foxp3)-positive Treg cells from non-Treg cell precursors. The induced Treg cells home specifically to the lungs and draining lymph nodes and have greatly potentiated suppressive activity compared with that seen in Treg cells purified from control mice. Induction of Treg cells is mediated by tolerogenic DCs generated after IVIG exposure. Compared with albumin-treated, OVA-exposed mice, IVIG-primed DCs express altered Notch ligands, including increased Delta-4 and reduced Jagged-1 levels, reflecting decreased T(H)2 polarization. Furthermore, IVIG-primed DCs can stimulate Treg cell differentiation from uncommitted Foxp3(-)CD4(+) T cells ex vivo, and adoptive transfer of IVIG-primed DCs abrogates airway hyperresponsiveness and induces Treg cells. CONCLUSION The anti-inflammatory effects of IVIG therapy can be mediated by the immunomodulation of DCs, creating a bridge that induces antigen-specific, highly suppressive Treg cells.

Biological and Phenotypic Alterations of T Cells in Aging

The deleterious effects of ageing on the T cell compartment are well studied, as they lead to increased susceptibility to infections, cancers, and autoimmunity in elders. Ageing reduces the number and T cell potential of hematopoietic precursors, and involution of the thymus renders it less capable of supporting de novo T cell development. Consequently, ageing compromises the functions of lymphocytes, resulting in a T cell pool with restricted receptor specificity and fewer naive T cells.

Age-Related Alterations in Regulatory T Cells

Age-associated impaired function of the immune system seems to be a major contributory factor to the increased frequency of morbidity and mortality. Ageing affects different immune cell types, including hematopoietic stem cells, lymphoid progenitors in the bone marrow and thymus, thymic stromal cells, mature lymphocytes in secondary lymphoid organs, and elements of the innate immune system. Importantly, significant alterations are seen in the T lymphocyte compartment. Age-related alterations are evident in all stages of the T cell development making them a significant element in immunosenescence. Recent studies showed that T regulatory cells, a subset of CD4+ T cells with immunoregulatory activities, are also affected by ageing. The age-related alterations of Tregs, mechanisms underlying Treg homeostasis, and functions in ageing are described in this chapter.

Assessment of the immune-modulatory activity of sialylated fraction of IVIg in a murine model of allergic asthma

Methods Mice were sensitized (i.n.) with OVA and then received IVIg or sialic acid enriched IVIg (SA-IVIg) fragments (i.p.), and then underwent challenge (i.n.). The induction of CD4CD25Foxp3Treg was determined by flowcytometry. AHR was measured, using a flexiVent small animal ventilator. Phenotypic properties of dendritic cells (DC) from various experimental groups were assessed by flow-cytometry. Expression of DCIR on DC was evaluated by flowcytometry and ICC. Adoptive transfer of DC was carried out to show the tolerogenic activity of IVIg-primed DC.