Studies were performed to examine the human immune response in normal individuals and in patients with congenital and acquired immunodeficiency states associated with a high frequency of cancer. We have focused our current studies on patients with X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD), X-linked hyper-IgM syndrome (XLM), X-linked lymphoproliferative syndrome (XLP), common variable immunodeficiency disease (CVID), the Wiskott-Aldrich syndrome (WAS) and selective IgA deficiency. X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) shares many features with the more common X-linked agammaglobulinemia (XLA) or Bruton's disease caused by mutations in Bruton's tyrosine kinase (Btk). We have shown XLA/GHD to be distinct from XLA since the former patients have no abnormalities in Btk expression including normal catalytic activity. We are currently examining additional X-chromosome genes as the cause of XLA/GHD as they become available as part of the Human Genome Project. We have shown that patients with XLM have markedly reduced cytokine production in response to T-cell activation and that this could be restored with the addition of recombinant CD40L trimer (CD154). These studies suggest the therapeutic possibility of CD154 administration for XLM. These observations are the scientific basis for a new clinical protocol and patients with XHM are currently being treated with recombinant CD154 in the Clinical Center. Recently two other groups cloned the gene responsible for XLP. This gene, termed SH2D1A, has no clearly defined function. We are currently examining the function of this gene. Several studies have suggested a genetic basis for CVID. To gain possible insight into aberrant gene expression, we are using cDNA microarrays to analyze differential gene expression in stimulated CVID and normal B-cells. A recently identified member of the tumor necrosis factor family, termed BLyS, drives B-cell proliferation and immunoglobulin secretion in vitro and in vivo. We have recently shown that a subset of patients with CVID can be stimulated with BLyS in vitro to proliferate and secrete antibodies. We have initiated a clinical trial NCI 02-C-0009 treating IgA deficient patients in vivo with BLyS. We continue to study the function of the Wiskott-Aldrich syndrome protein (WASp). These studies include demonstration of the expression of WASp in primary human megakaryocytes, platelets and monocytes. Moreover, we have identified two additional WASp-interacting proteins using the yeast two-hybrid system. Finally, using retroviral mediated gene therapy we have corrected the phenotypic abnormalities in Wiskott Aldrich syndrome patients' cells. Recently we have identified three patients with spontaneous genetic """"""""reversions"""""""" where the reverted cells appear to have a selective growth advantage in vivo. These results suggest that gene therapy might be used for the treatment of the Wiskott-Aldrich syndrome.
| Wada, Taizo; Konno, Akihiro; Schurman, Shepherd H et al. (2003) Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest 111:1389-97 |
