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Biomedical subjects

Alain Fischer

Publications and source records attributed to Alain Fischer.

At least 37 records · Page 2Linked to original sources
PubMed2006

Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections.

Major histocompatibility complex class II deficiency, a rare autosomal recessive primary immunodeficiency, is caused by the defective expression of human leucocyte antigen (HLA) class II molecules due to mutated trans-acting elements of any one of four regulatory genes (CIITA, RFXANK, RFX5, RFXAP). The impaired CD4 T-cell differentiation and antigen presentation in the periphery results in a severe defect of cellular and humoral response consistent with severe recurrent infections, leading to a poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative approach, but the overall cure rate is lower than in other immunodeficiencies. We report a single centre experience of 17 HSCTs with 15 HLA-identical donors between 1981 and 2004. Eight patients survived, while the occurrence of acute graft-versus-host disease (GVHD) was 50%. This study aimed to identify potential risk factors for GVHD and outcome within pre-HSCT complications related to the immunodeficiency. Five of seven patients with pre-existing viral infections developed acute GVHD > or = grade II, of whom four died. Two of seven patients without detectable pre-existing viral infection developed GVHD > or = grade II, and one died. The difference was significant (P < 0.05). A plausible link with other factors potentially associated with the development of GVHD could not be found. We suggest that the reduced survival after HLA-identical HSCT may be caused by the high incidence of pre-existing viral infections and associated with the onset of severe acute GVHD.

Acute Disease↗
PubMed2006

[Deficient expression of leukocyte adhesion proteins. A new Tunisian case].

Leukocyte adhesion deficiency (LAD) is a rare primary immunodeficiency inherited as an autosomal recessive genetic disorder. LAD was suspected in a four days old girl. She was born from healthy first cousins. A family history of a boy who died from omphalitis and sepsis was reported. Our patient had the severe form, she had delayed umbilical cord separation and suffered recurrent infections. She had a deletion of the G at position 1497. The patient received bone marrow transplantation from her HLA-identical mother at age of 14 months. She is now 9 years old and in good health.

Bone Marrow Transplantation↗
PubMed2005

Burkholderia pseudomallei infection in chronic granulomatous disease.

Melioidosis is a severe illness caused by Burkholderia pseudomallei, a sepsis-causing bacterial pathogen that is common in East Asia. We reexamined the underlying diagnosis in a 12-year-old boy who was diagnosed in the French West Indies with melioidosis when he was 4 years old. Our investigations led to the determination of chronic granulomatous disease (CGD), an inherited condition characterized by phagocytic cell dysfunction. This is the third reported case of melioidosis associated with CGD to be reported, lending support to an association between the two. The molecular determinants of the susceptibility of CGD patients to B. pseudomallei are still unknown. Our report suggests that CGD should be suspected in children with melioidosis, both in the Americas and probably in other regions world-wide.

Child↗
PubMed2005

Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study.

B-cell posttransplantation lymphoproliferative disorder (B-PTLD) is a rare but severe complication of transplantation, with no consensus on best treatment practice. This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Forty-six patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%. We conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.

Adolescent↗
PubMed2005

Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies.

BACKGROUND: The use of monoclonal antibodies against interleukin-2 receptor (IL-2R)-alpha chains could be an effective treatment of acute graft-versus-host disease (GvHD). Experimental model and clinical studies have reported various results. METHODS: Inolimomab is a murine anti-IL-2R. Eighty-five patients were evaluated retrospectively for the safety and efficacy of inolimomab given for the treatment of steroid-resistant acute GvHD (aGvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Diseases were immune deficiency, hematological malignancies, or solid tumors. Seventy-six percent of the patients received a myeloablative regimen. The source of HSCT was bone marrow for 45 patients, peripheral blood for 36 patients, and cord blood for 4 patients. Donors were 49 siblings and 36 unrelated. Acute GvHD was diagnosed within a median of 28 days after transplantation (grade II, 26 patients; grade III, 26 patients; grade IV, 33 patients). Inolimomab was administered in the event of steroid-resistant aGvHD with a median dose of 0.468 mg per kg (median period of treatment: 18 days). RESULTS: Twenty-five complete responses and 29 partial responses (total response rate: 63%) were observed with no side effects. There was no correlation between aGvHD grading and quality of response. Better responses were observed in cutaneous aGvHD. The overall survival probability was 26% (median follow-up: 20 months). Fifty-seven percent of patients died of toxicity related mortality, mostly aGvHD. Response to inolimomab seemed sustained (11% relapse in responders). CONCLUSION: Inolimomab is well-tolerated and effective for severe steroid-resistant aGvHD. The optimum regimen remains to be defined.

Acute Disease↗
PubMed2005

Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity.

Severe combined immunodeficiency (SCID) caused by mutations in RAG1 or RAG2 genes is characterized by a complete block in T- and B-cell development. The only curative treatment is allogeneic hematopoietic stem cell transplantation, which gives a high survival rate (90%) when an HLA-genoidentical donor exists but unsatisfactory results when only partially compatible donors are available. We have thus been interested in the development of a potential alternative treatment by using retroviral gene transfer of a normal copy of RAG1 cDNA. We show here that this approach applied to RAG-1-deficient mice restores normal B- and T-cell function even in the presence of a reduced number of mature B cells. The reconstitution is stable over time, attesting to a selective advantage of transduced progenitors. Notably, a high transgene copy number was detected in all lymphoid organs, and this was associated with a risk of lymphoproliferation as observed in one mouse. Altogether, these results demonstrate that correction of RAG-1 deficiency can be achieved by gene therapy in immunodeficient mice but that human application would require the use of self-inactivated vector to decrease the risk of lymphoproliferative diseases.

Animals↗
PubMed2005

Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn.

SAP is an adaptor protein that is expressed in NK and T cells. It is mutated in humans who have X-linked lymphoproliferative (XLP) disease. By interacting with SLAM family receptors, SAP enables tyrosine phosphorylation signaling of these receptors by its ability to recruit the Src-related kinase, Fyn. Here, we analyzed the role of SAP in NK cell functions using the SAP-deficient mouse model. Our results showed that SAP was required for the ability of NK cells to eliminate tumor cells in vitro and in vivo. This effect strongly correlated with expression of CD48 on tumor cells, the ligand of 2B4, a SLAM-related receptor expressed in NK cells. In keeping with earlier reports that studied human NK cells, we showed that SAP was necessary for the ability of 2B4 to trigger cytotoxicity and IFN-gamma secretion. In the absence of SAP, 2B4 function was shifted toward inhibition of NK cell-mediated cytotoxicity. By analyzing mice lacking Fyn, we showed that similarly to SAP, Fyn was strictly required for 2B4 function. Taken together, these results provide evidence that the 2B4-SAP-Fyn cascade defines a potent activating pathway of natural cytotoxicity. They also could help to explain the high propensity of patients who have XLP disease to develop lymphoproliferative disorders.

Adaptor Proteins, Signal Transducing↗
PubMed2005

B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil.

The generation of high-affinity antibodies requires somatic hypermutation (SHM) and class switch recombination (CSR) at the immunoglobulin (Ig) locus. Both processes are triggered by activation-induced cytidine deaminase (AID) and require UNG-encoded uracil-DNA glycosylase. AID has been suggested to function as an mRNA editing deaminase or as a single-strand DNA deaminase. In the latter model, SHM may result from replicative incorporation of dAMP opposite U or from error-prone repair of U, whereas CSR may be triggered by strand breaks at abasic sites. Here, we demonstrate that extracts of UNG-proficient human B cell lines efficiently remove U from single-stranded DNA. In B cell lines from hyper-IgM patients carrying UNG mutations, the single-strand-specific uracil-DNA glycosylase, SMUG1, cannot complement this function. Moreover, the UNG mutations lead to increased accumulation of genomic uracil. One mutation results in an F251S substitution in the UNG catalytic domain. Although this UNG form was fully active and stable when expressed in Escherichia coli, it was mistargeted to mitochondria and degraded in mammalian cells. Our results may explain why SMUG1 cannot compensate the UNG2 deficiency in human B cells, and are fully consistent with the DNA deamination model that requires active nuclear UNG2. Based on our findings and recent information in the literature, we present an integrated model for the initiating steps in CSR.

B-Lymphocytes↗
PubMed2005

Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia.

OBJECTIVE: To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells. DESIGN AND SETTING: Ex-vivo culture and gene transfer procedures were performed at The Children's Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available. PATIENT: A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation. PROCEDURE: CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human gamma c (the common gamma chain of several interleukin receptors; mutations affecting the gamma c gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 x 10(6) CD34+/gamma c+ cells/kg) were returned to the infant via a central line. RESULTS: T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 x 10(9) CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy. CONCLUSIONS: This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant's NK+ phenotype may also have exerted an effect.

Antigens, CD34↗
PubMed2005

Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome.

Three patients with Chediak-Higashi syndrome underwent allogeneic bone marrow transplantation between the ages of 2 years 9 months and 7 years. The outcome was uneventful, with sustained mixed chimerism. No subsequent recurrent infections or hemophagocytic syndrome were observed. At the age of 22 to 24 years, these 3 patients developed a neurologic deficit combining difficulty walking, loss of balance, and tremor. Neurologic evaluation demonstrated cerebellar ataxia and signs of peripheral neuropathy. Moderate axon loss and rarefaction of large myelinated fibers were observed on semithin sections of peripheral nerve. Cerebellar atrophy was detected by cerebral magnetic resonance imaging in 2 patients. We also reviewed the very long-term outcome of the other 11 patients with Chediak-Higashi syndrome who had received bone marrow transplants at our center since 1981. All displayed neurologic deficits or low cognitive abilities.

Adult↗
PubMed2005

Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product.

SAP is an adaptor protein expressed in T cells and natural killer cells. It plays a critical role in immunity, as it is mutated in humans with X-linked lymphoproliferative syndrome (XLP), a fatal immunodeficiency characterized by an abnormal response to Epstein-Barr virus (EBV) infection. SAP interacts with the SLAM family receptors and promotes transduction signal events by these receptors through its capacity to recruit and activate the Src kinase FynT. Because it has been previously established that FynT is selectively required for the development of NKT cells, we examined NKT cells in SAP-deficient mice and in humans with XLP. In the absence of SAP, the development of NKT cells is severely impaired both in mice and in humans. These results imply that SAP is a potent regulator of NKT cell development. They also identify for the first time a defect in NKT cells associated with a human primary immunodeficiency, revealing a potential role of NKT cells in the immune response to EBV.

Animals↗
PubMed2005

Failure of SCID-X1 gene therapy in older patients.

Gene therapy has been shown to be a highly effective treatment for infants with typical X-linked severe combined immunodeficiency (SCID-X1, gammac-deficiency). For patients in whom previous allogeneic transplantation has failed, and others with attenuated disease who may present later in life, the optimal treatment strategy in the absence of human leukocyte antigen (HLA)-matched donors is unclear. Here we report the failure of gene therapy in 2 such patients, despite effective gene transfer to bone marrow CD34(+) cells, suggesting that there are intrinsic host-dependent restrictions to efficacy. In particular, there is likely to be a limitation to initiation of normal thymopoiesis, and we therefore suggest that intervention for these patients should be considered as early as possible.

Adult↗
PubMed2005

Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2.

Autosomal recessive form of hyper-IgM syndrome type 2 (AR-HIGM2) is secondary to mutations affecting both alleles of AICDA gene encoding activation-induced cytidine deaminase, characterized by defects of immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) in most of the patients. We herein report the immunological phenotype of seven patients carrying a single heterozygous R190X mutation in AICDA. Variable defect in in vivo CSR inherited as an autosomal dominant (AD) trait strongly suggests that this heterozygous AICDA mutation causes HIGM (AD-HIGM2). In AD-HIGM2 B cells, CSR was consistently found impaired in vitro. However, in contrast to AR-HIGM2, the CSR-induced double-stranded DNA breaks in the switch region of IgM heavy chain gene were detected. The SHM frequency in V regions of IgM heavy chain gene in B cells was normal in all (but one patient). The characteristics of the AD-HIGM2 phenotype indicate that the AID C-terminal region may be involved in DNA repair machinery required for CSR.

Adolescent↗
PubMed2005

CD3 deficiencies.

PURPOSE OF REVIEW: The molecular characterization of inherited T-cell immunodeficiencies has contributed to delineating key factors in human T-cell development. This review reports on the recent description of deleterious mutations in the genes encoding CD3 subunits expressed at the T-lymphocyte membrane in association with the T-cell receptor. RECENT FINDINGS: Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype. Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes. These results contrast with the partial T-cell immunodeficiency caused by a deficiency in CD3G. SUMMARY: Two new severe combined immunodeficiency conditions have been reported as a consequence of either CD3D or CD3E deficiency. The distinct phenotype of CD3G deficiency sheds light on the differential roles of CD3 subunits in T-lymphocyte development.

CD3 Complex↗
PubMed2005

Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects.

Hyper-immunoglobulin M (IgM) syndromes are primary immunodeficiencies characterized by normal or elevated serum IgM levels with the absence of other isotypes, pinpointing to a defect in the Ig class switch recombination (CSR). The delineation of hyper-IgM syndromes made it possible to better define the mechanisms underlying the two major events of antibody maturation in humans, CSR and introduction of somatic hypermutation (SHM) in the variable region of immunoglobulins. The description of the activation-induced cytidine deaminase (AID) deficiency, characterized by a defect in both CSR and SHM, demonstrated for the first time that this molecule acts as a master player in the antigen-induced Ig gene-modification events responsible for both CSR and SHM. However, deleterious mutations located in the C-terminus lead to a CSR defect without affecting SHM, providing evidence for a role of AID in CSR distinct from the cytidine deaminase activity, likely by binding to a specific CSR cofactor. Molecular causes of two other hyper-IgM conditions have not yet been defined. However, they may be caused by either a defect in AID targeting on S regions or a CSR-specific DNA-repair defect. The mechanism of action of AID remains somewhat debated, but the observation that uracil-DNA-glycosylase deficiency leads to a severe hyper-IgM syndrome strongly argues in favor of a DNA-editing activity of AID.

B-Lymphocytes↗
PubMed2005

Severe combined immunodeficiency. A model disease for molecular immunology and therapy.

Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.

Genetic Therapy↗