![]() ![]() ![]() ![]() Similar content being viewed by othersĪdenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is a primary immunodeficiency characterized by severe pan-lymphopenia (T −, B − and NK −), severe and recurrent infections, failure to thrive and death in the first year of life, if left untreated 1, 2. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. ![]()
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