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Biomedical subjects

W Friedrich

Publications and source records attributed to W Friedrich.

At least 73 records · Page 4Linked to original sources
PubMed1994

Bone marrow transplantation for autosomal recessive osteopetrosis. A report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group.

The outcomes of 69 patients who received allogeneic bone marrow grafts for autosomal recessive osteopetrosis in the period between 1976 and 1994 were analyzed retrospectively. Four patients received bone marrow transplants (BMT) without prior myeloablative conditioning; transient osteoclast function was demonstrated in one of them. Sixty-five patients received myeloablative pretreatment. Recipients of a genotypically human leukocyte antigen (HLA)-identical BMT had an actuarial probability for 5-year survival, with osteoclast function, of 79%; recipients of a phenotypically HLA-identical bone marrow graft from a related or unrelated donor, or one HLA-mismatched graft from a related donor, had an actuarial probability for 5-year survival, with osteoclast function, of 38%; patients who received a graft from an HLA-haplotype mismatched related donor had a probability for 5-year survival of only 13%. The main problems in haplotype-nonidentical BMT were graft failure and BMT-related complications such as sepsis, bleeding, and interstitial pneumonia. Osteoclast function developed in all patients with full engraftment. Recovery of osteoclast function was associated with severe hypercalcemia in 24% of the patients with engraftment, especially those older than 2 years of age. At the time of BMT, severe visual impairment was present in 35% of the patients; of the 15 patients who had visual impairment at the time that a successful BMT was performed, two had improvement after BMT (13%). Within the total group, one patient had neurodegeneration. Engraftment of healthy donor cells had no influence on the progression of that abnormality and BMT thus had no beneficial effect on this phenotype of osteopetrosis. In general, however, early BMT remains the only curative treatment for autosomal recessive osteopetrosis.

Actuarial Analysis↗
PubMed1993

X-linked lymphoproliferative disease. Detection of a paternally inherited mutation in a German family using haplotype analysis.

OBJECTIVE: To study the inheritance of the X-linked lymphoproliferative disease (XLP) locus in a German family. DESIGN: Haplotype segregation analysis. SETTING: Departments of Pediatrics and Human Genetics, University of Würzburg and University of Ulm, Federal Republic of Germany. PARTICIPANTS: Fourteen members of a family with XLP. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Using molecular genetic techniques, we diagnosed the XLP status of the members of a German family. Restriction fragment length polymorphism analysis with closely linked polymorphic X-chromosomal DNA markers (Xq25-q27) revealed XLP carrier status in a female infant. Moreover, the XLP mutation was suggested to have occurred in the germ cell of the grandfather. CONCLUSION: This is the first report of a paternally inherited XLP mutation. The recurrence risk for germ cell mosaicism in XLP may be similar to that of X-linked Duchenne muscular dystrophy.

Base Sequence↗
PubMed1992

Allorecognition and T cell repertoire selection in severe combined immunodeficiency lacking HLA class II antigens.

In order to elucidate the role of HLA class II molecules in generation of self-nonself discrimination of human T cells, we have analyzed T cell functions in an HLA class II-negative severe combined immunodeficiency patient. Patient PBL expressed no HLA-DR, -DQ, and -DP antigens as judged by immunofluorescence using mAb, and failed to elicit MLR responses from unrelated controls. Patient PBL contained mature T cells (CD3+ TCR alpha beta+) of the CD4 and CD8 subset, showing an apparently normal TCR diversity, as judged by use of anti-V beta 5, -V beta 6, -V beta 8, -V beta 12, and -V alpha 2 mAb. Patient PBL proliferated in response to anti-TCR/CD3 mAb and PHA, but not against recall Ag, despite immunization, and mounted proliferative, but not cytotoxic, responses against allogeneic cells. To find out whether the MLR responses were a consequence of self-nonself discrimination, the patient HLA-DR and -DQ genotype was determined using sequence specific oligonucleotide probes, revealing DRB1*0401 DQB1*0301 alleles, and MLR were set up against a panel of HLA-DR4 DQw3 stimulators matched or mismatched for DRB1*0401 DQB1*0301. Results showed no MLR against DRB1*0401 DQB1*0301 stimulators, but significant responses against stimulators expressing DRB1*0408 and/or DQB1*0302 alleles. Moreover, the DRB1*0401 DQB1*0301 APC reconstituted proliferation of patient PBL against PPD; this response was completely blocked by an anti-IL-2R (p55) mAb and partially also by anti-HLA-DR and -DQ mAb, indicating recognition of these molecules as restriction element presenting Ag--i.e., as self--by patient T cells. In conclusion, the novel demonstration of self-nonself discrimination by T cells from an HLA class II-negative SCID patient suggests that it may not be absolutely dependent on regular HLA class II expression within the differentiation environment in humans.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

[Severe combined immune defect. Presentation of exfoliative dermatitis with eosinophilia and lymphadenopathy].

BACKGROUND: We report on 9 infants with severe combined immunodeficiency (SCID), who additionally showed signs of Omenn syndrome with an exfoliative dermatopathy, alopecia, enlarged lymph nodes, a hepatomegalia and a striking blood eosinophilia. The immunological evaluation revealed the characteristic abnormalities of SCID with cellular and humoral immunodeficiency. All patients however had the unusual finding of mature T cells in the peripheral blood. By HLA typing these cells were noted to be of maternal origin in 5 patients. In the other 4 patients the T cells were of host origin. We asked for additional differences between both patient groups. METHOD: Both patient groups were analyzed and compared with regard to case histories, clinical, laboratory and histopathological parameters. RESULTS: No clinical or laboratory differences could be detected. The histomorphologic analysis of patients with or without maternal T cells was identical. The skin biopsies showed dense cell infiltrations of lymphocytes, histiocytes and eosinophils, in the enlarged lymph nodes the latter two cell types predominated. Therefore the only difference between the 2 patient groups was the presence or absence of maternal T cells. CONCLUSION: Since the Omenn syndrome is found in association with maternal as well as patient derived T cells, we postulate that the peculiar symptoms of this syndrome are the result of a T cell induced inflammatory reaction, similar but not identical to a graft versus host reaction, occurring on the basis of an inborn SCID.

Bone Marrow↗
PubMed1991

Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study.

Fifty-one children between 26 and 214 months of age (median, 100 months) with acute lymphoblastic leukemia (ALL) were grafted in second remission from HLA-identical sibling donors (except for two patients who were grafted with a marrow with 1 antigen-mismatch). Initial treatment and relapse therapy were similar in all patients according to the BFM- and CoALL-protocols (front line: 38 patients according to BFM-protocols and 13 patients according to CoALL-protocols; relapse: 12 patients in study ALL-REZ-BFM 83, 17 in ALL-REZ-BFM 85, 20 in ALL-REZ-BFM 87, and two in ALL-REZ-BFM 90). The conditioning regimens were different, consisting of cyclophosphamide (CY) total body irradiation (TBI) plus (n = 27), VP-16-TBI (n = 23), and CY-TBI and ARA-C (n = 1). Three patients had a second graft after conditioning with CY-TBI for the first transplantation. The second ablative regimen consisted of CY plus VP-16 in the first patient and CY plus busulfan in the two other patients, one of whom relapsed again. All patients but three had bone marrow (BM), either isolated or combined, relapses. Twenty-nine of the patients are in continuous complete remission (CCR), ranging from 1 to 67 months after transplantation with a median time of 30 months. One patient was lost to follow-up in continuous remission. Nine patients died from treatment-related complications (infections and graft-versus-host disease) and 12 patients suffered a leukemic relapse; three of them received a second graft and two are in CCR. Kaplan-Meier analysis yields an event-free survival (EFS) of 0.52 +/- 0.08. The probability of a 7-year relapse-free interval (RFI) is 0.68 +/- 0.08. EFS for patients with late relapses is 0.47 +/- 0.12 and for patients with early relapses 0.56 +/- 0.1. The RFI for patients with late relapses is 0.65 +/- 0.12 and for patients with early relapses 0.69 +/- 0.11. There is a nonsignificant trend towards superior results for patients grafted after conditioning with VP-16 plus TBI. When all patients who are not in CCR at day +125 (which is the median interval between relapse diagnosis and BM transplantation [BMT]) are excluded from the chemotherapy results, there is no significant difference between the results of BMT and chemotherapy for late relapses. On the other hand, there is a significant advantage between chemotherapy and BMT for early relapses over chemotherapy (P less than or equal to .01).

Adolescent↗
PubMed1991

Severe combined immunodeficiency (SCID) in man: B cell-negative (B-) SCID patients exhibit an irregular recombination pattern at the JH locus.

Human severe combined immunodeficiency (SCID) patients were analyzed by a polymerase chain reaction assay for their recombination capability at the DHQ52-JH region of the immunoglobulin heavy chain locus. Five patients with B cells (B+ SCID) exhibited a recombination pattern also observed in healthy persons. In contrast, six patients lacking B cells (B- SCID) showed a grossly altered rearrangement pattern characterized by the (partial) absence of regular DHQ52-JH recombinations and the presence of abnormal rearrangements. These events were caused by deletions surpassing the boundaries of immunoglobulin coding elements and thus resemble the pattern of deletional recombinations previously described in SCID mice.

B-Lymphocytes↗
PubMed1991

Expansion of a maternally derived monoclonal T cell population with CD3+/CD8+/T cell receptor-gamma/delta+ phenotype in a child with severe combined immunodeficiency.

The diagnosis of severe combined immunodeficiency complicated by chronic graft-vs-host disease affecting liver and skin in association with engraftment of maternal T cells was established in a 5-mo-old boy. Detailed immunologic and molecular genetic studies were performed because a unique T cell phenotype was identified on initial evaluation. A major proportion of the patient's peripheral T cells expressed a CD8+ and TCR-gamma/delta+ phenotype while CD4+ T cells were virtually absent. Southern blot analysis of cell subpopulations isolated by fluorescence activated cell sorting indicated that approximately 50% of CD8+/TCR-gamma/delta+ cells were clonally related. Immunophenotyping and -genotyping also identified a clonal TCR-gamma/delta+ cell population in the child's mother. Clonal identity of these T cell populations in mother and child was demonstrated by studies using a clonspecific TCR-delta probe generated by polymerase chain reaction as well DNA sequence analysis. HLA typing and DNA fingerprinting confirmed that the child had acquired this clone diaplacentally from the mother. According to immunohistology and DNA analysis the clone was found to be virtually absent in the liver tissue suggesting that this clonal T cell population plays a minor role, if any, in the pathogenesis of the liver abnormalities in the patient. In the mother the CD8+/TCR-gamma/delta+ clone spontaneously declined to a level around 1% of PBMC several months later and has remained at this level since. We conclude that 1) a clonal expansion of TCR-gamma/delta T cells, triggered by yet unknown stimuli, may occur in otherwise healthy individuals, 2) respective T cells are able to cross the placental barrier, and 3) in an microenvironment precluding rejection, i.e., in severely immunocompromised patients, these cells may persist and even represent a significant proportion of circulating T cells.

Alleles↗
PubMed1991

Limited T cell receptor diversity of transplacentally acquired maternal T cells in severe combined immunodeficiency.

Circulating maternal T lymphocytes were noted in the peripheral blood of six patients with severe combined immunodeficiency. Phenotypical analyses revealed the presence of both CD4 and CD8 subsets in some but not all cases. The maternal T cells could be stimulated by anti-TCR/CD3 mAb +/- rIL-2, but were virtually silent in the MLR and against the recall Ag purified protein derivative of tuberculin and tetanus toxoid, even in immunized patients engrafted with T cells from a responding mother. Using a panel of mAb against TCR V region gene encoded epitopes including V beta 5, V beta 6, V beta 8, V beta 12, and V alpha 2, we show that maternal T cells displayed a profoundly reduced TCR diversity, characterized by a lack of one or even several TCR V subsets in all six cases and a dramatic (5- to 25-fold) expansion of other TCR V subsets in three cases. In one patient analyzed, limited TCR diversity was also seen in T cells cultured from bone marrow and skin; restimulation experiments of these cells against cells expressing host MHC Ag were unsuccessful, as were attempts to exclusively allocate anti-host proliferative responses of maternal control T cells to the TCR V subsets that had undergone expansion in vivo. We conclude that a severely reduced TCR diversity is a common feature of maternal T cells engrafted in severe combined immunodeficiency patients. These novel findings provide a structural basis to understand the failure of these cells to protect the host from infections and may also help to understand their relative inefficiency to induce lethal, multi-organ, graft vs host disease. Moreover, as an experiment of nature, the reported phenomenon clearly illustrates the functional consequences in vivo of an insufficient TCR diversity.

Antibodies, Monoclonal↗
PubMed1991

Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report.

Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti-LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus-induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.

Antibodies, Monoclonal↗
PubMed1991

Self-nonself discrimination and repertoire selection of human T cells differentiated in an HLA-semiallogeneic environment following bone marrow transplantation for severe combined immunodeficiency.

We have analyzed allorecognition, HLA restriction and T cell receptor (TcR) diversity in an HLA-heterozygous (HLA-DRw6,7) severe combined immunodeficiency (SCID) patient whose T cell system had been repopulated by HLA-homozygous (HLA-DRw6) paternal T cells following T cell-depleted bone marrow transplantation (BMT). Donor origin of T cells and host origin of antigen-presenting cells (APC) in peripheral blood and BM is shown by HLA typing of separated cell populations and two-color immunofluorescence using an anti-HLA monoclonal antibody (mAb). Peripheral blood lymphocytes (PBL) from the chimeric patient proliferate normally against PHA, anti-TcR/CD3 mAb, pooled allogeneic PBL, and also against the recall antigen (Ag) tetanus toxoid and purified protein derivative of tuberculin (PPD) following immunization, suggesting recognition by donor (DRw6) T cells of Ag presented by host (DRw6,7) APC. PPD-specific cytotoxic T lymphocytes generated in vitro from patient PBL post-BMT display specific cytotoxicity against targets expressing DRw6 and DR7, but not against DR-mismatched targets, suggesting that HLA restriction of Ag recognition may occur through determinants expressed by the host and not by the donor. Donor T cells differentiated in the HLA-semiallogeneic host show specific proliferative and cytotoxic responses against HLA-mismatched stimulators, but not against stimulators taken from the host, expressing the host-specific HLA-haplotype, or expressing the host-specific HLA-DR7 antigens. Compared to T cells directly taken from the donor, differentiation of donor T cells in the host is associated with a significant decrease of T cells expressing TcR V beta 5 and V alpha 2 determinants, while no differences in the abundance of of TcR V beta 6, V beta 8 and V beta 12 subsets were noticed. We conclude that allorecognition, major histocompatibility complex (MHC) restriction and TcR diversity generation of human T cells can be modulated through differentiation in an MHC-different environment, as had been previously shown to be the case in murine model systems.

Antigen-Presenting Cells↗
PubMed1991

Fatal B-cell lymphoproliferative syndrome in allogeneic marrow graft recipients. A clinical, immunobiological and pathological study.

We have studied four cases of fatal B-cell lymphoproliferative syndrome (LPS) developing among 333 patients (incidence 1.2%) treated with allogeneic bone marrow transplantation (BMT). All four patients had received a T-cell depleted graft. Onset of the first clinical symptoms (palpable lymph node enlargement in three and IgA-lambda paraproteinemia in two patients) occurred between 41 and 188 days post-BMT (median 76 days). The course of the LPS was rapidly progressive in all cases, leading to death in 2-5 weeks. The peripheral blood showed progressive pancytopenia with disproportionally high numbers of activated NK cells, apparently compensating for the T-cell deficiency. Post-mortem histological studies disclosed polymorphic B-cell proliferations, most pronounced in the lymph nodes, spleen, liver, lungs and kidneys. Lymphohemopoietic cells were of donor origin in three patients. In the fourth patient, graft failure suggested a host origin for the proliferating cells. Immunophenotyping and gene rearrangement analysis revealed polyclonal proliferation in one patient, monoclonal proliferation in another patient, and an oligoclonal pattern in the other two patients. The clinical behavior of the LPS was independent of clonality. Immunohistologically, the proliferating cells showed characteristics of relatively mature B-cells in three cases, and pre-B-cell features in one case. Epstein Barr virus (EBV) serology indicated seroconversion (primary infection) in one child, and chronic active EBV infection in both adults. EBV DNA as well as EBV nuclear antigen (EBNA) were detected in infiltrated tissues of all four patients. The labeling pattern on in situ hybridization suggested a replicative EBV infection comparable to that in lymphoblastoid cell lines. We conclude that EBV-associated LPS developing as a result of post-transplant immunodeficiency is a distinct clinicopathologic entity, differing from non-Hodgkin's lymphoma (including Burkitt's lymphoma) and infectious mononucleosis of the immunocompetent host.

Adult↗
PubMed1991

Stimulation of human T cells via anti-T cell receptor monoclonal antibody BMA031: distinct cellular events involving interleukin-2 receptor and lymphocyte function antigen 1.

We have analyzed activation of resting human T cells by anti-T cell receptor (TCR) monoclonal antibody (mAb) BMA031, a murine mAb of the G2b isotype. Human peripheral blood lymphocytes (PBL) respond to anti-TCR mAb by short-term proliferation in vitro and by acquisition of responsiveness to interleukin 2 (rIL-2) in the absence of detectable IL-2 production. Cell depletion and limiting dilution experiments indicate that anti-TCR mAb +/- rIL-2 stimulation covers a substantial portion of human T cells, including CD4+ and CD8+ cells. Enhancement by rIL-2 of anti-TCR mAb-induced proliferation is blocked by anti-IL-2 receptor (IL-2R, p55) mAb, while anti-TCR mAb-induced proliferation is not. In contrast, anti-TCR mAb-induced proliferation is blocked by anti-lymphocyte function antigen 1 (LFA-1, CD11a) mAb and is not demonstrable in PBL from two patients with severe congenital LFA-1 deficiency, not even in the presence of irradiated LFA-1+ PBL. We conclude that stimulation of resting human T cells by anti-TCR mAb BMA031 enables dissociation of distinct steps in T cell activation that specifically require participation of IL-2R (p55) and LFA-1 cell surface molecules in a mutually exclusive way.

Antibodies, Monoclonal↗
PubMed1991

Stable engraftment of allogeneic T lymphocytes in a patient with severe combined immunodeficiency following a transfusion with unirradiated blood. Specific recognition of host histocompatibility antigens and engraftment failure of a bone marrow transplant HLA-identical to the host.

We have analyzed the immunocompetence of blood donor-derived, allogeneic T cells that had engrafted in a patient with severe combined immunodeficiency following transfusion with unirradiated blood. The blood donor T cells multiply and persist in the patients' bone marrow and peripheral blood over several months without leading to a graft-versus-host disease. The allogeneic T cells can be expanded in vitro and restimulated by cells expressing host HLA-DR antigens. The presence of blood donor-derived T cells prevented engraftment of a bone marrow graft from an HLA-identical sibling; in contrast, engraftment and immunological reconstitution by bone marrow donor-derived cells was seen following elimination of the allogeneic T cells in vivo. We conclude that the allogeneic T cells sensitized against host histocompatibility antigens were responsible for bone marrow graft failure, even though this sensitization did not lead to a graft-versus-host disease.

Antilymphocyte Serum↗