T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase.

Abstract

Adenosine deaminase (ADA) deficiency causes severe combined immune deficiency (SCID) by interfering with the metabolism of deoxyadenosine, which is toxic to T lymphocytes at all stages of differentiation. Enzyme replacement with polyethylene glycol-modified ADA (PEG-ADA) has been previously shown to correct deoxyadenosine metabolism and improve mitogen-induced T lymphocyte proliferation. We studied the biochemical and immunologic effects of PEG-ADA in two infants with ADA-deficient SCID. While in a catabolic state, higher doses of PEG-ADA than previously described were required to normalize deoxyadenosine metabolism. After biochemical improvement, the patients recovered immune function in a pattern similar to that observed in normal thymic ontogeny and in patients with immunological reconstitution after bone marrow transplantation. Immune reconstitution was marked by the sequential appearance in the peripheral blood of phenotypic T lymphocytes corresponding to successive stages of thymic differentiation. Functional reconstitution was marked by the successive appearance of mitogen responses dependent on exogenous in vitro IL-2, mitogen responses not requiring exogenous IL-2, antigen-specific responses dependent on exogenous IL-2, and finally, antigen-specific responses not requiring exogenous IL-2. Natural killer function was tested in one patient and normalized with PEG-ADA therapy. Optimal PEG-ADA therapy appears to normalize thymic differentiation in ADA-deficient SCID, resulting in normal antigen-specific immune function. (J. Clin. Invest. 1993. 92:596-602.)

T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates

“…These findings confirm that PEG-ADA does not enter erythrocytes, and indicate that there was minimal production of ADA from the transduced gene in erythrocytes. Because the RBC of the patients were deficient in ADA enzymatic activity, it seems that the reduced dosages of PEG-ADA provided adequate plasma ADA enzymatic activity to prevent detectable dAXP accumulation in RBC (consistent with experience in other patients [11][12][13] …”

“…Cells isolated by ficoll-hypaque or FACS sorting were frozen as cell pellets for subsequent DNA or RNA analysis. Immunophenotypic analyses of PBMC were done using fluorescentlylabeled monoclonal antibodies as described 12 . Blastogenic responses of PBMC to PHA and tetanus toxoid were measured by 3 H-thymidine incorporation as described 12 .…”

“…Immunophenotypic analyses of PBMC were done using fluorescentlylabeled monoclonal antibodies as described 12 . Blastogenic responses of PBMC to PHA and tetanus toxoid were measured by 3 H-thymidine incorporation as described 12 . Plasma levels of ADA enzymatic activity and erythrocytic levels of deoxyadenosine nucleotides were measured as described 12 .…”

“…Blastogenic responses of PBMC to PHA and tetanus toxoid were measured by 3 H-thymidine incorporation as described 12 . Plasma levels of ADA enzymatic activity and erythrocytic levels of deoxyadenosine nucleotides were measured as described 12 . Semi-quantitative PCR of leukocyte DNA and RT-PCR of RNA to determine the frequency of peripheral blood leukocytes containing and expressing the LASN vector were done as described 6 .…”

Interleukin-7 and Immunorestoration in HIV: Beyond the Thymus

“…1). Prevailing evidence suggests that in clinical settings wherein thymic function is robust, regeneration of new T cells through the thymus rapidly restores normal T cell numbers and repertoire diversity (1)(2)(3). However, due to thymotoxic effects of the virus itself (4) as well as ongoing immune responses directed toward the virus, hosts with less than robust thymic function are more commonly encountered in the setting of HIV infection.…”