Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed‐onset adenosine deaminase deficiency

Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, Miyawaki T. Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed‐onset adenosine deaminase deficiency. Abstract: In this case report, we describe successful BMT with RIC in a patient with delayed‐onset ADA deficiency. A three‐yr‐old Japanese boy was diagnosed with delayed‐onset ADA deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present. At four yr of age, he underwent BMT with a RIC regimen, including busulfan and fludarabine, from an HLA‐identical healthy sister. Engraftment after BMT was uneventful without GVHD. Decreased ADA levels in blood immediately increased following BMT, and the patient was disease‐free 13 months after BMT. These results suggest that BMT with RIC may sufficiently restore immune regulation in delayed‐onset ADA deficiency. A longer follow‐up period is needed to confirm these observations.     

Successful management of neutropenia in a patient with CD40 ligand deficiency by immunoglobulin replacement therapy

Hyper-IgM syndromes are characterized by profound reduction of serum IgG, IgA, and IgE levels with normal or increased concentrations of serum IgM. CD40 ligand deficiency is X-linked form of the disease, which results in a lack of immunoglobulin class switching from IgM to IgG in B cells. In addition to the recurrent infections, a number of patients suffer from neutropenia. There are some evidences indicating the effect of G-CSF in combination with intravenous immunoglobulin (IVIG) in improvement of neutrophil counts, which has become the most common procedure to control neutropenia. In this report we present a 6 year-old patient of CD40 ligand deficiency, who suffered from chronic, severe neutropenia. Administration of IVIG was started for him when the diagnosis was made at the age of 1.5 years and he was on the regular IVIG therapy after that time untill now for a period of 4.5 years. IVIG and prophylactic antibiotic therapy, despite cessation of granulocyte colony-stimulating factor, injection after one month, corrected the severe neutropenic state of this patient. It seems that regular administration of sufficient doses of IVIG can be useful in the management of neutropenia in CD40 ligand deficiency, which results in better quality of life with decreasing occurrence of infection.     

Outcome of Non-T-Cell-Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation from Family Donors in Children and Adolescents

Non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (SCT) from family members has been reported, but its effectiveness and safety are not fully known. In this study, we examined the outcomes of 83 children and adolescents with nonmalignant (n = 11) or malignant (n = 72) disorders who underwent SCT mismatched at 2 or 3 HLA loci, either from the mother (n = 56), a noninherited maternal antigen (NIMA)-mismatched sibling (n = 14), or the father/a noninherited paternal antigen (NIPA)-mismatched sibling (n = 13). Engraftment was satisfactory. Severe (grade III-IV) acute graft-versus-host disease (GVHD) was noted only in malignant disease, with an incidence of 21 of 64 evaluable patients. GVHD prophylaxis with a combination of tacrolimus and methotrexate was significantly associated with a lower risk of severe acute GVHD, compared with other types of prophylaxis(P = .04). Nine of 11 patients with nonmalignant disease and 29 of 72 patients with malignant disease were alive at a median follow-up of 26 months (range, 4-57 months). Outcomes were not significantly different among the 3 donor groups (mother versus NIMA-mismatched sibling versus father/NIPA-mismatched sibling) for the malignancy disorders. Our results indicate that non-T-cell-depleted HLA-haploidentical SCT may be feasible, with appropriate GVHD prophylaxis, for young recipients who lack immediate access to a conventional stem cell source.     

The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils

The function of the kinase Btk in neutrophil activation is largely unexplored. Here we found that Btk-deficient neutrophils had more production of reactive oxygen species (ROS) after engagement of Toll-like receptors (TLRs) or receptors for tumor-necrosis factor (TNF), which was associated with more apoptosis and was reversed by transduction of recombinant Btk. Btk-deficient neutrophils in the resting state showed hyperphosphorylation and activation of phosphatidylinositol-3-OH kinase (PI(3)K) and protein tyrosine kinases (PTKs) and were in a 'primed' state with plasma membrane-associated GTPase Rac2. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. Our data identify Btk as a critical gatekeeper of neutrophil responses.     

Maternal germinal mosaicism of X‐linked agammaglobulinemia

X‐linked agammaglobulinemia (XLA) is an immunodeficiency caused by abnormalities in tyrosine kinase (BTK), and is characterized by a deficiency of peripheral blood B cells. We studied cytoplasmic expression of BTK protein and analyzed the BTK gene (BTK) in peripheral blood mononuclear cells from two siblings with XLA and additional family members. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient with XLA. A single base deletion (C563) in BTK‐exon 6, which encodes the TH domain, was identified in both XLA patients. However, normal cytoplasmic expression of BTK protein in monocytes was detected in their mother without any BTK mutation. These results strongly suggest germinal mosaicism in the mother. © 2001 Wiley‐Liss. Inc.