The goal of this project is to identify and characterize the genetic basis for certain of the primary immunodeficiency disorders, which are associated with an increased incidence of cancer. While these disorders are rare, their study has been extremely instructive in defining previously unsuspected elements of importance in human immune function. The Immunophysiology Section conducts a clinical translational research program. Basic observations in the laboratory on recombinant immunostimulatory molecules have led to two clinical trials. A clinical trial (00-I-006) of recombinant CD40 ligand (CD40L) in patients with CD40L deficiency (XHIM, OMIM 308230) and a clinical trial of BLySTM in patients with selective IgA deficiency (OMIM 137100) have both been successfully completed with full patient accrual. Further clinical trials in patients with XHIM and selective IgA deficiency are currently being planned. Studies of the Wiskott-Aldrich syndrome (WAS) and the responsible gene (WASP) have continued. The hypothesis is that an understanding of WASP protein function(s) would provide insight into the molecular mechanisms underlying the WAS and provide important clues for innovative diagnostic and therapeutic strategies. Using monoclonal antibodies to WASP produced in the laboratory, we identified several proteins, which interacted with the WASP protein and played critical roles in cytoskeletal organization and function. We took this knowledge to the clinic to see what insights the patients might provide which could yield unique insights into a molecular understanding of the WASP protein. One of the difficulties in understanding the WAS is that no one center could accumulate sufficient patients to define the full genetic and clinical spectrum of the disease. We were interested in whether there was a correlation between the genetic mutations, which occurred in the patients, and the clinical phenotype that was observed. To accomplish this goal, the Section helped organize a large consortium, which was able to accumulate molecular and clinical data on 262 patients from 227 families. This study provided valuable information about the spectrum and frequency of the genetic defects occurring in patients and the clinical spectrum of the WAS as well as correlations between the genetic defects and the clinical disease. To further advance these studies, we used a monoclonal anti-WASP antibody to develop a strategy to measure WASP protein expression at the single cell level using multicolor cell surface and intracellular flow cytometry. We were able to measure WASP expression in the peripheral blood cells of normal individuals and document deficient WASP expression in cells from WAS patients. Moreover, this deficient expression could be corrected by allogeneic bone marrow transplantation. Bone marrow transplantation has been used as the definitive treatment of the WAS since the late 1970s. Using a somewhat empiric pre-transplant conditioning regimen, Major Histocompatibility Complex (MHC)-matched, MHC- haploidentical, and matched-unrelated hematopoetic stem cell donors have been used with varying success. While these transplants were successful to varying degrees, there was sparse data regarding what was necessary or sufficient in terms of engraftment to obtain a good clinical outcome. Moreover, there was little data about the durability of engraftment or the cell lineages engrafted. Using the available flow cytometric test for WASP expression, we studied 12 patients following allogeneic bone marrow transplantation. Six were fully engrafted with donor cells while six were a mixture of donor and host cells (chimeric) in various cell lineages. These results suggested that additional studies of bone marrow transplants in the WAS would be useful in defining the optimal conditions for bone marrow transplantation.
| 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 |
