Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.

Impairment of purine metabolism due to adenosine deaminase (ADA) deficiency is associated with a severe combined immunodeficiency (SCID). Polyethylene glycolmodified ADA (PEG-ADA) has provided noncurative, life-saving treatment for these patients, but full immune recovery is not achieved with this therapy. Since ADA-SCID is perhaps the most difficult form of SCID to handle clinically, understanding the benefits and limitations of PEG-ADA therapy may be relevant for treatment selection. To this purpose, we analyzed the rate of thymic output, T and B cell repertoires, number of T cell divisions, IFN-c and IL-4 production, and the extent of cell death in five ADA-SCID patients following a prolonged period of treatment with PEG-ADA. We found that thymic output was low in these patients. However, their T cell repertoire was heterogeneous, and their T lymphocytes produced cytokines upon activation and responded to mitogen stimulation, although with different kinetics. Furthermore, a high number of peripheral T lymphocytes were committed to apoptosis. Anomalies were also observed in the B cell compartment, with oligoclonal expansions of B cell clonotypes in two patients. Our data indicate that decreased thymic function, B cell oligoclonality, and increased spontaneous apoptosis may be the mechanisms by which the immunodeficiency of ADA-SCID patients persists in spite of treatment with PEG-ADA.

A major feature of the immature immune system in the newborn is its inability to produce significant levels of immunoglobulins other than IgM in response to antigens. It has recently been demonstrated that interaction of the CD40 molecule on B cells with the CD40 ligand (CD40L) on activated T cells is pivotal for immunoglobulin switching. In view of these findings, we have tested cord blood mononuclear cells (CBMC) for expression of CD40L. Our data clearly demonstrate that freshly isolated CBMC do not express significant levels of CD40L upon in vitro activation; this defect is intrinsic to CD4+ cord blood lymphocytes. In vitro priming of CBMC with phytohemagglutinin and interleukin-2 for several days induced a conversion from the "naive" to the "memory" phenotype (as assessed by expression of CD45 isoforms) and led to substantial CD40L expression upon appropriate restimulation. These data indicate that ineffective CD40L expression might represent a major factor for reduced immunoglobulin production in the neonate, and suggest that antigenic exposure in vivo leads to changes in the genetic program, enabling T cells to express CD40L.

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