Biomedical subjects

G Annett

Publications and source records attributed to G Annett.

9 recordsLinked to original sources

PubMed2000

T cell depleted haploidentical bone marrow transplantation for the treatment of children with severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is fatal in early childhood if unrecognized and if not treated. The aim was to determine the efficacy of T cell depleted bone marrow transplantation (TCD BMT) in the treatment of children with SCID. Eleven children diagnosed with SCID received histocompatible related donor bone marrow transplantation--HRD BMT (group I). Thirty seven children diagnosed with SCID who did not have histocompatible donors were treated with TCD haploidentical parental bone marrow transplantation (BMT) (group II). TCD was performed by in vitro soybean lectin agglutination followed by E-rosette depletion. Patients were longitudinally assessed for the presence and function of T and B lymphocytes. In group I all children survived. The mean age of children in this group at the time of HRD BMT was 15.4 months. All surviving patients normalized their specific T cell function. Two out of 11 require treatment with intravenous immunoglobulin i.v. Ig. In group II 17 out of 37 (46%) children survived. At the time of TCD BMT the mean age of survivors was 7.5 months, vs. 11.4 months in patients who died. Death was caused most commonly by opportunistic infections, Epstein-Barr virus induced lymphoproliferative disease (EBV-LPD), and graft versus host disease (GvHD). Seventeen out of 17 surviving patients recovered normal numbers of CD3+ cells and antigen specific T cell function. Five out of 17 never recovered their B cell function and require i.v. Ig injections. Early diagnosis, prevention or treatment of opportunistic infections, and enhancement of immune recovery will be necessary to improve survival in patients with SCID treated with TCD BMT.

Adolescent↗

PubMed1999

Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count.

IL-7 is produced by stromal cells and is the major lympho- and thymopoietic cytokine. IL-7 induces proliferation and differentiation of immature thymocytes, and protects thymocytes from apoptosis by induction of bcl-2 expression. The regulation of IL-7 production is poorly characterized, although down-regulation by transforming growth factor-beta (TGF-beta) has been described. We measured the serum levels of IL-7 before and after bone marrow transplant (BMT) in 32 children undergoing BMT for genetic diseases (severe combined immune deficiency (SCID) and thalassemia), aplastic anemia, and acute lymphoblastic and non-lymphoblastic leukemia (ALL and ANLL). Prior to BMT, the highest IL-7 levels were observed in patients with SCID and ALL, i.e. those patients with genetic or acquired lymphopenia. Patients with thalassemia and ANLL had normal levels of IL-7. Over the 8 weeks following BMT, the IL-7 levels of patients with SCID and ALL fell as the absolute lymphocyte count (ALC) increased. No detectable change in IL-7 levels was observed in the patients with thalassemia and ANLL. Levels of IL-7 were highest in the young infants with SCID compared to the age-matched controls. Together, the data demonstrate that serum levels of IL-7 in lymphopenic patients are inversely related to patient age and the absolute lymphocyte count (ALC). The inverse relationship to ALC suggests that there is either direct regulation of stromal production or more likely, binding of secreted IL-7 to lymphocytes expressing IL-7 receptors.

Adolescent↗

PubMed1999

Localization of a gene for Duane retraction syndrome to chromosome 2q31.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.

Amino Acid Substitution↗

PubMed1998

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

Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for gene-corrected T lymphocytes, which may overcome inefficient gene transfer. Four years after three newborns with this disease were given infusions of transduced autologous umbilical cord blood CD34+ cells, the frequency of gene-containing T lymphocytes has risen to 1-10%, whereas the frequencies of other hematopoietic and lymphoid cells containing the gene remain at 0.01-0.1%. Cessation of polyethylene glycol-conjugated adenosine deaminase enzyme replacement in one subject led to a decline in immune function, despite the persistence of gene-containing T lymphocytes. Thus, despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect.

Adenosine Deaminase↗

PubMed1995

Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency.

Haematopoietic stem cells in umbilical cord blood are an attractive target for gene therapy of inborn errors of metabolism. Three neonates with severe combined immunodeficiency were treated by retroviral-mediated transduction of the CD34+ cells from their umbilical cord blood with a normal human adenosine deaminase complementary DNA followed by autologous transplantation. The continued presence and expression of the introduced gene in leukocytes from bone marrow and peripheral blood for 18 months demonstrates that umbilical cord blood cells may be genetically modified with retroviral vectors and engrafted in neonates for gene therapy.

Adenosine Deaminase↗

PubMed1995

The effect of thymic function on immunocompetence following bone marrow transplantation.

We investigated the role of thymic function in the immunodeficiency that characterizes bone marrow transplantation (BMT) recipients. The capacity of histocompatible BMT recipients to generate new CD4+ T lymphocytes was determined by FACS analysis with antibodies to the two isoforms of CD45: CD45RA, which is expressed on newly generated CD4 T lymphocytes, and CD45RO, which is expressed on antigen-specific memory CD4 T lymphocytes. Immediately following BMT, all patients had low levels of CD45RA-expressing CD4 T lymphocytes, which increased during the first year and then stabilized. Since thymic function decreases with age in normal individuals, the impact of recipient age on the generation of new CD45RA,CD4 T lymphocytes was determined in BMT recipients with and without chronic graft-vs.-host disease (GVHD). In addition, antigen-specific immune function was determined by assessing in vitro blastogenic response to tetanus toxoid (TT). More than 1 year after transplantation, the results from BMT recipients without chronic GVHD were similar to those of normal individuals; there was an age-dependent decline in the number of CD45RA,CD4 T lymphocytes, and antigen-specific immune function was age-independent. On the other hand, recipients with chronic GVHD had an age-dependent decline in their immune function (r = 0.45 and p = 0.02) that correlated with the number of new CD45RA,CD4 T lymphocytes (p = 0.027) but not the number of memory CD45RO,CD4 T lymphocytes (p = 0.11). Thus recipients with chronic GVHD have decreased antigen-specific immune function that may be due to an acceleration of the normal thymic aging process induced by GVHD and its therapy.

Bone Marrow Transplantation↗

PubMed1994

Immunophenotypic differences between putative hematopoietic stem cells and childhood B-cell precursor acute lymphoblastic leukemia cells.

Acute leukemia cells express myeloid, B-lymphoid and T-lymphoid lineage specific antigens. Many acute leukemias express the hematopoietic progenitor cell antigen CD34. Three proposed models of the normal human hematopoietic stem cell include CD34+ Thy-1low Lin-, CD34+ CD38-, and CD34+ HLA-DR-. The patterns of expression of CD34, Thy-1, CD38, HLA-DR, and multiple lineage-specific antigens on 49 consecutive pediatric B-cell precursor acute lymphoblastic leukemia (ALL) cases submitted for immunophenotyping (36 at first diagnosis, 13 at relapse) were analyzed. CD34+ expression was observed in 67% of the cases. CD34+ expression correlated with Thy-1low expression and expression of myeloid antigens (p < 0.001 and < 0.025, respectively). The CD34+ Thy-1low phenotype was observed in 65% of the cases; the CD34+ CD38- or CD34+ HLA-DR- phenotypes were observed in only three cases. Examples of heterogeneous expression of CD34 and Thy-1 were found in six cases, but CD38 expression was always bright and homogeneous in all positive cases. The data from this analysis indicates that the CD34+ CD38- or CD34+ HLA-DR- phenotypes would be more useful than the CD34+ Thy-1low phenotype for distinguishing normal hematopoietic stem cells from leukemic cells in childhood B-cell precursor ALL.

ADP-ribosyl Cyclase↗

PubMed1992

Correction of antigen-specific T-lymphocyte function by recombinant cytokines in children infected with human immunodeficiency virus type 1.

To determine the role of cytokines in the immunodeficiency of children infected with human immunodeficiency virus type 1 (HIV-1), we compared the antigen-specific (tetanus toxoid-induced) T-lymphocyte blastogenesis of HIV-1-infected patients with and without the addition of exogenous interleukin-1 and interleukin-2. Acquisition of in vitro antigen-specific immunologic function was seen in some patients after the addition of exogenous cytokines. The antigen-specific immunodeficiency in some HIV-1-infected children is due to defects in cytokine production rather than to an absence of antigen-specific T lymphocytes.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purged marrows for children with acute non-lymphoblastic leukemia in second remission.

Although autologous bone marrow transplantation (ABMT) following purging with 4-hydroperoxycyclophosphamide (4HC) has been effective for some adults with acute non-lymphoblastic leukemia (ANLL), there are few data on ABMT for children. We have performed ABMT for 13 patients (median age, 5 years) with ANLL in second remission. Bone marrow was treated ex vivo with 4HC to kill residual leukemic cells. In order to enhance the anti-leukemic effect of 4HC, exogenous red blood cells were eliminated from the marrow/4HC mixture. All patients were conditioned for transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg), followed by infusion of the 4HC treated marrow. Eleven of 13 patients had complete hematologic reconstitution; there were no transplant-related deaths. Five patients relapsed at 2, 4, 5, 6 and 6 months post-BMT. Eight patients are disease-free survivors; the median time for survival is 24 months, with a projected disease-free survival of 61%. ABMT is a safe and efficacious treatment modality for children with ANLL in second remission. Our results suggest that the disease-free survival for pediatric patients may be superior to that seen in adults.

Actuarial Analysis↗