The Interaction of Innate and Adaptive Immunity and Stabilization of Mast Cell Activation in Management of Infusion Related Reactions in Patients with Fabry Disease

Abstract

Fabry disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA gene resulting in lack of or faulty α-galactosidase A (α-GalA) enzyme. Enzyme replacement therapy (ERT) with recombinant human α-GalA enzyme (agalsidase) is the standard treatment option for FD. Infusion-related reactions (IRRs), with symptoms ranging from rigors, to fever, pain, vomiting, angioedema and diarrhea, are often seen due to immune response against the exogenous enzyme. To elucidate the mechanisms causing the IRRs in FD, eight patients who developed IRRs were investigated. All, except one, tested negative for agalsidase-specific IgE and had normal tryptase levels. Circulating dendritic cells were drastically reduced during IRRs, suggesting possible sequestration to the sites of inflammation. An increase in NK cells and a decrease in T cells were also observed. Cytokines IL-4, IL-8 and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells. All IRRs were managed successfully using a combination of standard premedications and mast cell stabilizers without any interruption of therapy. Taken together, the results indicate crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation. Mast cell stabilizers could be used to control IRRs and for safe reintroduction of agalsidase in patients previously treated with ERT.

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

“…In this study the authors further demonstrated that circulating dendritic cells were drastically reduced during IARs, suggesting their possible sequestration to the sites of inflammation [39]. An increase in natural killer cells and a decrease in T cells was also observed [39]. In addition, cytokines IL-4, IL-8, and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells, indicating a crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation [39].…”

“…However, a recent study identified only 25% of patients with IARs with reduced C4 levels, suggesting that the primary cause for IARs is not complement-mediated cytotoxic hypersensitivity reactions [39]. In this study the authors further demonstrated that circulating dendritic cells were drastically reduced during IARs, suggesting their possible sequestration to the sites of inflammation [39]. An increase in natural killer cells and a decrease in T cells was also observed [39].…”

“…An increase in natural killer cells and a decrease in T cells was also observed [39]. In addition, cytokines IL-4, IL-8, and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells, indicating a crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation [39].…”

“…Symptoms are generally limited to fever and/or chills and require premedication with anti-histamines and steroids and a decreased infusion rate [36]. In addition to milder symptoms such as urticarial skin lesions, facial flushing or swelling, headache, and pain in the limbs, more severe IARs have been reported with chest and throat tightness, dyspnea, hypotension, and life-threatening anaphylactic reactions [37][38][39][40]. According to the manufacturer's instructions, 24% of patients treated with agalsidase-alfa and 67% of patients treated with agalsidase-beta can suffer from these adverse effects.…”

“…According to the manufacturer's instructions, 24% of patients treated with agalsidase-alfa and 67% of patients treated with agalsidase-beta can suffer from these adverse effects. According to the literature, IARs are mainly the result of anaphylactoid (IgE-independent) rather than anaphylactic (IgE-mediated type 1 hypersensitivity) reactions, since only few affected patients were positive for IgEs against recombinant AGAL [21,39,[41][42][43][44]. The risk for IARs seems to be increased in patients with anti-agalsidase IgG antibodies [5,36].…”