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D Schendel

Publications and source records attributed to D Schendel.

At least 19 recordsLinked to original sources
PubMed2004

Public health monitoring of developmental disabilities with a focus on the autism spectrum disorders.

Developmental disabilities (DDs) are conditions characterized by physical, cognitive, psychological, sensory, adaptive, and/or communication impairments manifested during development. Approximately 17% of individuals in the United States 18 years and younger have a DD, and for most children the cause of their condition is unknown. Of particular interest are the autism spectrum disorders (ASDs), characterized by unusual social, communication, and behavioral development. Previously autism was thought to be a rare condition, but the number of children receiving services for an ASD has increased dramatically in the last decade. Concerns about increases in DDs, particularly ASDs, their causes, and the high costs of intervention have highlighted the need for systematic public health monitoring. Service provider data, such as annual reporting of special education services or of state DD programs, do not provide a complete estimate of the rates for DDs, including ASDs. Unlike genetic metabolic disorders or congenital hearing loss (HL) for which newborn screening programs can provide accurate prevalence rates, there are currently no genetic or biologic markers for the ASDs to enable consistent and early identification of affected children. Centers for Disease Control and Prevention's (CDC) Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) is a model for population monitoring of ASDs/DDs that has been implemented in other states. This article discusses the role of ASD/DD tracking in public health, as well as the challenges of ASD/DD tracking, including case definition and identification, associated conditions, linkages, and data access.

Autistic Disorder↗
PubMed2001

Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant.

Human adenovirus (AdV) infection and EBV-lymphoproliferative disease (LPD) are serious complications following allogeneic stem cell transplantation. In the healthy individual these viruses cause minor, self-limiting diseases but in the immunocompromised patient they are responsible for significant morbidity and mortality. The limitations of anti-viral drugs and a better understanding of the cellular immune response to viral pathogens have prompted interest in developing adoptive immunotherapy for transplant patients. Ex vivo expanded cytotoxic T lymphocytes (CTLs) specific for EBV have been used effectively both as prophylaxis against EBV-LPD and as treatment of established EBV+ lymphoma. To generate CTLs specific for AdV, we infected immature dendritic cells with virus, in the presence of lipid, and subsequently used these cells to stimulate PBMNCs. Cytotoxicity assays showed that the resulting CTLs specifically lysed AdV-expressing targets and that this was mediated predominantly by CD4+ T cells. To generate CTLs specific for both AdV and EBV, we developed a CD40 ligand co-culture system to infect B-lymphoblastoid cell lines (LCLs) with high efficiency. PBMNCs from healthy AdV-seropositive donors were stimulated weekly with autologous AdV+-LCLs. Chromium release assays demonstrated that the resultant CTLs had specificity against both EBV and AdV and that this was mediated by both CD4+ and CD8+ T cells. Our findings have potential implications for post-transplant AdV and EBV immunotherapy in recipients of allogeneic stem cell transplants.

Adenoviridae↗
PubMed2000

Reconstitution of the cellular immune response after autologous peripheral blood stem cell transplantation in patients with non-Hodgkin's lymphoma.

Peripheral blood stem cell (PBSC) transplants may be depleted of lymphoid progenitors, thereby disabling the cellular immune response against viral pathogens after autologous PBSC transplantation (PBSCT). To monitor the cellular immune reconstitution after autologous PBSCT, we investigated the cytolytic activity (CLA) of peripheral blood T lymphocytes against Epstein-Barr virus (EBV) in 13 patients with non-Hodgkin's lymphoma or multiple myeloma. The individual EBV-directed CLA (EBV-CLA) was determined by calculating the number of cytolytic effector cells in 106 T cells needed to lyse 25% of autologous EBV-transformed B-lymphoblastoid cells, expressed as lytic units (LU25). During the first 6 months after PBSCT, the EBV-CLA was only 14.6% of the response of healthy controls (median 4. 8 vs. 32.9 LU25). Thereafter, the EBV-CLA increased to 28.15 LU25 (median) or 86% of healthy controls. Monthly follow-up analyses in five selected patients showed that the EBV-CLA was barely detectable at 4 weeks and recovered at 8-12 weeks after PBSCT in four out of five patients. Effector cells consisted mostly of CD8-positive T lymphocytes, with small CD4- and CD3/CD56-positive lymphocyte fractions. These results suggest that the reconstitution of the cellular immune response against EBV takes 8-12 weeks after autologous PBSCT.

Female↗
PubMed2000

Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis.

In patients with myeloid malignancies, cell-mediated immunity is often suppressed, being most profound in those with advanced disease. Such immune dysfunction, as demonstrated in many patients with chronic lymphocytic leukaemia (CLL) and myelodysplastic syndrome (MDS), may, at least in part, be due to altered expression of the CD3-zeta chain, which is an important component of the T-cell receptor (TCR). We speculated that impaired expression of the TCR-zeta chain would be evident in peripheral blood T cells of patients with chronic myeloid leukaemia (CML) and that such an abnormality would result in an increased ex vivo susceptibility to apoptosis. In this study, we demonstrated that, compared with normal controls, zeta chain expression was significantly downregulated in all of the T-cell subsets (P < 0.009) in more than 90% of CML patients. In addition, there was a significantly lower expression of the CD3-epsilon chain (P < 0.001) in patients than in controls. In those patients with abnormal zeta chain expression, the proportion of lymphocytes with spontaneous DNA fragmentation, as determined by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assays, was also significantly higher (P < 0.002) than controls. From all of the patients tested, it was possible to upregulate partially zeta chain expression and hence to reduce the susceptibility to apoptosis by cross-linking the T cells with interleukin (IL)-2, interferon (IFN)-alpha or immobilized CD3. In addition, such cross-linked T cells showed a significantly higher capacity to proliferate than the native CML T cells.

Adult↗
PubMed1997

Mapping of HLA class I binding motifs in forty-four fusion proteins involved in human cancers.

Chromosomal translocations coding for abnormal proteins are present in several human cancers. The junctional region of fusion proteins represents a potential target for a T cell-mediated antitumor response. T lymphocytes recognize antigens in the form of short peptides that must bind to HLA molecules. Different HLA specificities can bind different peptides, thus depicting different "peptide binding motifs." It would be useful to know whether a certain fusion protein presents, within its fusion region, the binding motif(s) for a certain HLA molecule. This information would allow a more focused immunological analysis. Here we present data obtained from the screening of the fusion regions of 44 different fusion proteins for the presence of binding motifs to 34 class I HLA molecules, including all of the most frequently encountered specificities. A total of 201 independent peptides was identified (range, 0-11 peptides/fusion protein). A marked heterogeneity among the 44 different fusion proteins analyzed is evident. For example, the pml/RARalpha fusion protein present in acute promyelocytic leukemia presents no binding motif (BCR 3) at all or to a single HLA molecule (Cw*0301, BCR 1). Alternatively, the fusion proteins BCR/ABL, ALL1/AF-6, EWS/ATF-1, or NPM/ALK exhibit motifs for several common HLA specificities. Heterogeneity is also present inside a single translocation (in ALL1/ENL, for example, different subtypes match motifs with cumulative frequencies in the population from 108 to 0%). In two cases where the relative frequency of different fusion protein subtypes was available, a tendency toward an inverse relationship between frequency and the percentage of population covered by the identified binding motifs was observed. Peptides with motifs for HLA A*0201, A3, and Cw*0702 were also tested for actual binding using a stabilization assay; 13-40% showed significant HLA binding, using this assay. However, fewer fusion protein-derived peptides bound to HLA A*0201 and A3 than non-fusion protein-derived peptides. These data provide the first list of peptides derived from fusion proteins that may be assessed as potential tumor-specific antigens.

Amino Acid Sequence↗
PubMed1995

Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris.

Psoriasis vulgaris is an inflammatory skin disease characterized by excessively increased keratinocyte proliferation. Several lines of evidence support the idea that T cells infiltrating psoriatic skin lesions play a vital role in the pathogenesis of the disease. To establish whether lesional accumulation and activation of T lymphocytes reflect a specific local immune response, the TCR beta-chain variable (V beta) region gene usage was studied in chronic psoriatic plaques, normal skin, and paired blood lymphocytes. By semiquantitative PCR, we found that overexpression of either or both V beta 2 and V beta 6 gene families characterized the TCR repertoires of normal skin and psoriatic skin lesions. However, sequence analysis of the complementarity-determining region 3 (CDR3) of these V beta gene families demonstrated a marked TCR oligoclonality only in psoriatic lesions, not in normal skin or in blood lymphocytes. The amino acid sequences of the lesional TCR clones revealed that certain conserved junctional motifs were shared by different patients. A second biopsy taken from one of the psoriasis patients 18 mo later from a different anatomical site disclosed that the same TCR clones were again dominating. These data suggest that lesional psoriatic T lymphocytes expressing the prevailing TCR V beta genes represent an oligoclonal T cell subset that expanded from a few progenitor T cells in response to Ag in the skin of psoriasis patients. They are derived from a polyclonal T cell population that, by the expression of V beta 2 or V beta 6 TCR, appears to be predisposed for homing to the skin.

Adolescent↗
PubMed1994

T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells.

In various immunological disorders the pathomechanisms of tissue damage are causally associated with specific patterns of locally produced cytokines. To study the molecular and cellular mechanisms involved in the manifestation of psoriasis vulgaris we have assessed the cytokine mRNA profile expressed in lesional psoriatic skin and in T cell clones (TCC) that were established from skin lesions of patients with psoriasis. As demonstrated by use of the polymerase chain reaction (PCR), psoriasis lesions consistently exhibit transcription of a complex pattern of cytokines. It includes mediators selectively produced by T lymphocytes [interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, interleukin (IL)-2, IL-3 and IL-5] as well as cytokines secreted by various cell types [transforming growth factor (TGF)-alpha/-beta, TNF-alpha, IL-6/-8 and granulocyte-macrophage-colony stimulating factor], while IL-4 is missing. With the exception of TGF-alpha, this cytokine profile was also observed in lesional psoriatic T cell clones yielding supernatants mitogenic for keratinocytes in vitro (MTCC), but not in T cell clones yielding supernatants that inhibited keratinocyte proliferation (STCC). The congruent cytokine expression of psoriatic skin lesions and MTCC emphasizes that inflammation in psoriasis is driven by a sofar unrecognized regulatory T cell subset that may serve to control epidermal regeneration and convey immunosurveillance over epithelial surfaces. It is characterized by the combined expression of IFN-gamma, TGF-beta, IL-2 and IL-5 in the absence of IL-4 and by its selective capacity to enhance keratinocyte proliferation. This newly defined combination of regulatory properties of a distinct T cell population cannot be reconciled with an immune response of the T helper cells (TH)0, TH1 or TH2 type.

Base Sequence↗
PubMed1993

Allele-specific peptide ligand motifs of HLA-C molecules.

The consensus motifs of HLA-Cw3, -Cw4, -Cw6, and -Cw7 ligands were determined by pool sequencing. Together with information obtained by sequencing of some prominent individual peptides, the results indicate the following: (i) all four HLA-C molecules are associated with peptides. (ii) These peptides adhere to allele-specific motifs that are similar to those of to HLA-A or -B molecules; they have a preferred length of nine amino acids and an anchor residue at the C terminus. (iii) All four HLA-C molecules analyzed exhibit related peptide motifs, although each allelic product shows individual characteristics in fine specificity. (iv) Processing and origin of peptides appear not to be different from that of other class I molecules. (v) No obvious difference at C-terminal position 9 was present in the peptides isolated from the two dimorphic variants of HLA-C that determine dominant resistance to natural killer NK1-specific cells (HLA-Cw4, -Cw6) or to NK2-specific cells (HLA-Cw3, -Cw7) and that differ in two residues in or near the pocket at position 9.

Amino Acid Sequence↗
PubMed1992

The genetic basis of Ro and La antibody formation in systemic lupus erythematosus. Results of a multicenter study. The SLE Study Group.

Antibodies against Ro and La, including recombinant La and recombinant 60 kD-Ro, were determined by counter immunoelectrophoresis and ELISA in over 300 central European systemic lupus erythematosus (SLE) patients. The presence of both Ro and La antibodies was strongly associated with the MHC haplotype B8-C4AQ0-DR3-DQ2, the association being strongest for DR3. After exclusion of all B8-DR3 positive patients only DR3 positive patients still showed an increased incidence of Ro and La antibodies, suggesting DR3 as the primary association factor. High titers of La antibody, but not of 60 kD-Ro antibody, were also significantly associated with the presence of DR3. Other DR and DQ antigens or heterozygous DQ combinations were not significantly associated with Ro and La antibodies.

Antibodies, Antinuclear↗
PubMed1992

MHC associations of autoantibodies against recombinant Ro and La proteins in systemic lupus erythematosus. Results of a multicenter study. SLE Study Group.

Antibodies against recombinant 52 kD-Ro, recombinant 60 kD-Ro and recombinant La protein were determined by ELISA in over 300 central European patients with systemic lupus erythematosus (SLE). A strong association with HLA-DR3 was found for antibodies against 52 kD-Ro and La, but not for recombinant 60 kD-Ro antibodies in the absence of antibodies against 52 kD-Ro or La. Ro/La negative SLE patients still showed an increased frequency of HLA-DR3 as compared to healthy controls. These results indicated that the preferential formation of Ro and La antibodies was not due to an unspecific stimulatory effect of HLA-DR3 but that the antibody response to certain defined proteins (52 kD-Ro and La) was influenced by MHC genes in SLE. Furthermore, the association of SLE with HLA-DR3 was independent of the effects of DR3 on the formation of 52 kD-Ro and La antibodies.

Antibody Specificity↗
PubMed1992

Major histocompatibility complex haplotypes and complement C4 alleles in systemic lupus erythematosus. Results of a multicenter study.

In a multicenter study more than 300 central European systemic lupus erythematosus (SLE) patients were examined for HLA-B, HLA-DR, and complement C4 phenotypes. For 174 SLE patients MHC haplotypes were determined by family segregation analysis, and for 155 patients C4 gene deletions were determined by TaqI restriction fragment length polymorphism. Two haplotypes, B8-C4AQ0-C4B1-DR3 and B7-C4A3-C4B1-DR2, were identified as risk factors for SLE. These findings were confirmed by applying the haplotype frequency difference (HFD) method, which uses nontransmitted haplotypes from the family study as internal controls. Furthermore, only HLA-DR2, but not DR3, B7, or B8, was significantly increased in SLE patients independently of the two risk haplotypes. C4A gene deletions, but not silent C4AQ0 alleles, were increased in SLE patients and neither C4BQ0 alleles nor C4B gene deletions were increased. The observed frequencies of homozygosity and heterozygosity for the two haplotypes and the frequencies of homozygotes for C4AQ0 and C4A deletions did not differ from the expected values, indicating that the risk for SLE is conveyed by single allele effects. In conclusion, there are two MHC-linked susceptibility factors for Caucasian SLE patients carried by the haplotypes B7-DR2 and B8-DR3. The results argue against C4Q0 alleles being the decisive factors increasing susceptibility to SLE.

Alleles↗
PubMed1991

Immunoglobulin allotypes are not associated with HLA-antigens, autoantibodies and clinical symptoms in systemic lupus erythematosus. Members of the SLE Study Group.

Immunoglobulin heavy chain (G1m, G2m, G3m, A2m) and kappa light chain (Km) allotype and phenotype frequencies of 323 central European Caucasian patients with systemic lupus erythematosus (SLE) were examined and correlated with various genetic, serologic and clinical markers of SLE. No significant associations were found between immunoglobulin allotypes or phenotypes and all 20 parameters tested (nephritis, vasculitis, arthralgias, photosensitivity, discoid lesions, central nervous system disease, Raynaud's phenomenon, sex, anti-Ro, anti-La, anti-nRNP, HLA-DR1-DR7, HLA phenotypes B8-DR3, B7-DR2). It could therefore be assumed that Gm, A2m and Km allotypes were not associated with HLA-antigens and had no influence on the serologic and clinical expression of SLE.

Autoantibodies↗
PubMed1991

Hetero- and homozygosity of MHC class II gene products in systemic lupus erythematosus. The Members of the Deutsche Multizentrische SLE-Studie.

An analysis of HLA class II antigens in 356 white patients with systemic lupus erythematosus (SLE) showed that all HLA-DR and -DQ homozygous and heterozygous combinations appear with frequencies expected from the observed gene frequencies. HLA-DR2 and HLA-DR3 gene frequencies were both increased in SLE, as were the odds ratios of all DR2 and DR3 hetero- and homozygous combinations. HLA-DR2/C4AQ0 heterozygotes were also not increased over expected values. Therefore, gene complementation at MHC loci does not contribute to susceptibility to SLE, but rather one or two MHC allele(s) in linkage with HLA-DR2 and HLA-DR3.

Alleles↗
PubMed1989

Association of class I, II, and III MHC gene products with systemic lupus erythematosus. Results of a Central European multicenter study.

Class I, II, and III MHC gene products were examined in 248 Central European SLE patients. The previously reported association with HLA-A1, -B8 and -DR3, and C4AQ0 alleles was confirmed. The frequency of HLA-DR2 was also slightly elevated in SLE patients, while no increase in C4BQ0 alleles was observed. Additional findings were a significantly increased frequency of HLA-B13 and a significant decrease of HLA-B44.

Alleles↗
PubMed1987

Constitutive and induced expression of the individual HLA-DR beta and alpha chain loci in different cell types.

The HLA-DR subregion of the human major histocompatibility complex encodes molecules involved in the regulation of the immune response. These HLA class II molecules are transmembrane heterodimers composed of an alpha and a beta chain. The polymorphic beta chains are encoded by multiple, highly homologous loci, whereas the alpha chain is encoded by a single, nonpolymorphic locus. HLA-DR is expressed constitutively on B lymphocytes and on activated T lymphocytes. It can also be induced by interferon-gamma on most nonlymphoid cells. In a quantitative study of the expression of the individual DR beta chain loci, we have investigated: the levels of mRNA transcripts of the two functional DR beta loci (beta I and beta III) in B cells of various haplotypes; whether both beta chain loci are expressed in activated T cells and, if so, the level of expression of each; whether both loci are expressed in interferon-gamma-induced nonlymphoid cells. This analysis relied on locus-specific DR beta chain oligonucleotide probes. Expression of both the beta I and the beta III loci was observed in all cell types and in all haplotypes tested. In every case the amount of beta I mRNA was about 5 times higher than that of beta III mRNA. This indicates a controlled and coordinated regulation of the mRNA levels of these two HLA-DR loci under all conditions of major histocompatibility complex class II gene expression.

B-Lymphocytes↗
PubMed1981

[Bone marrow transplantation for aplastic anaemia (author's transl)].

From March 1975 until May 1980 twelve patients with severe aplastic anemia were grafted with bone marrow from HLA-identical siblings by the Munich Cooperative Group for Bone Marrow Transplantation. Six patients are alive between 10 months and more than 5 years after grafting with normal blood values and marrow. One patient is treated as an out patient for chronic localized graft-versus-host disease (GvHD), five patients are well and without treatment. Six patients have died, one patient with a cerebral hemorrhage the day before transplantation, three patients following rejection of grafts 32, 40 and 55 days after grafting, one patient with severe GvHD 85 days after grafting and one patient, probably with interstitial pneumonia, following cerebral hemorrhage. Three of 6 patients who were conditioned with Cyclophosphamide (CY) only died following rejection of the graft. Two adults who were conditioned with CY and "total lymphoid irradiation" and three children, who wer given unirradiated leukocyte concentrates from the marrow donor after grafting, did not reject their grafts. The results of the Munich-Cooperative Group for Bone Marrow Transplantation are comparable to those of large, specialized centers for bone marrow transplantation, they indicate possibilities of cure of severe aplastic anemia by marrow grafts from HLA-identical siblings. They confirm that better results are obtained with earlier transplantation in the course of the disease.

Adolescent↗