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Biomedical subjects

A H Filipovich

Publications and source records attributed to A H Filipovich.

At least 55 records · Page 3Linked to original sources
PubMed1991

Unrelated donor bone marrow transplantation for correction of lethal congenital immunodeficiencies.

The majority of children with lethal congenital immunodeficiencies lack histocompatible related bone marrow donors. T-cell depleted haploidentical parental bone marrow transplantation has been used successfully in selected patients with severe combined immunodeficiency (SCID), but it has not benefited most patients with other immunodeficiencies when it has been tried. For these reasons, we undertook a pilot study using closely matched unrelated donors for bone marrow transplantation of children with life-threatening primary immunodeficiencies. Unrelated donor searches were performed for 24 patients and one or more suitable donors were identified for 21 patients. Unrelated donor bone marrow transplantation (URD BMT) has been performed in 18 patients with various diagnoses: SCID (8), Wiskott-Aldrich syndrome (WAS) (2), Chediak-Higashi syndrome (CHS) (2), combined immunodeficiencies (3), Ataxia Telangiectasis (AT) (2), and one patient with combined immunodeficiency and large granular lymphocytosis (1). The overall actuarial survival rate is 59% with excellent results observed for infants with SCID and children with WAS and CHS.

Adolescent↗
PubMed1990

Epstein-Barr virus--determined clonality in posttransplant lymphoproliferative disease.

Analysis of the genomic termini of Epstein-Barr virus can provide valuable insight into the cofactor role of EBV in the development of B cell lymphomas and lymphoproliferative disease. We report EBV genomic findings in pathologic specimens from 10 patients who developed lymphoma or lymphoproliferative disease after renal or bone marrow transplantation. Endonuclease restriction patterns of EBV genomic termini are highly variable in size in both the episomal and linear configuration. This variability in fragment size permits direct assessment of tissue clonality in EBV-infected material. Hybridization with terminus-specific probes also reveals configuration of viral genome (circular and latent vs. linear and replicative). Nine of 10 patients had tumors with mono- or biclonal episomal markers, and 4 of 10 had evidence of linear or replicative virus. Analyses of virally determined markers were compared to immunoglobulin gene rearrangement studies, histologic immunophenotyping, cytogenetics, and clinical outcome. These 10 cases represent a spectrum of lymphoproliferative disorders ranging from benign polyclonal to malignant monoclonal disease. The molecular data lend credence to two important aspects of viral pathogenesis: (1) the finding of a homogeneous episomal population in the monoclonal tumors suggests that EBV infection is an early event in tumorigenesis that occurs before clonal expansion; and (2) therapeutic efficacy of acyclovir has been shown only in presence of polyclonal disease but may impact on intermediate stages where linear replicative virus can be found. Finally, the various assessments of tumor clonality were compared, and although heterogeneity was seen among patients and among diagnostic methods, analyses at the molecular level using virus and immunoglobulin gene specific probes were concurrent and provide the more sensitive means for detection of clonality.

Adolescent↗
PubMed1990

Prevention of graft rejection in allogeneic bone marrow transplantation. II. Preclinical studies with three radiation protocols.

Three radiotherapeutic regimens were compared in vitro to determine their immunosuppressive potential against non-MHC-restricted cytotoxic cells. Assays of natural killer and lymphokine-activated killer function, and cytotoxicity against allogeneic cells were used to quantitate the cytotoxic potential of peripheral blood mononuclear cells from healthy individuals following irradiation with a single dose of 1000 cGy on day 0, 1320 cGy of fractionated radiation (165 cGy b.i.d. x 4 days), or "split-dose" irradiation consisting of 1000 cGy on day 0 followed 5 or 7 days later by 500 cGy. Both irradiated and nonirradiated (control) PBMC cultures were maintained in culture with medium containing interleukin-2, immunophenotyped, and assayed for cytotoxicity from 1 to 8 days after irradiation. Single dose and fractionated-dose irradiation resulted in a progressive decline in cytotoxic capacity, with an 80% inhibition of both NK and LAK cell activity 8 days after onset of irradiation. The split dose of 500 cGy administered 7 days after a dose of 1000 cGy was found to be the most effective in eliminating NK (93% inhibition) and LAK (100% inhibition) cytotoxicity. These data indicate that split-dose irradiation may result in greater immuno-suppression than single-dose or fractionated irradiation.

Bone Marrow Transplantation↗
PubMed1990

T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation. The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease.

Twenty-nine patients with advanced leukemias (median age 34 years) received histocompatible sibling marrow that had been depleted of T cells by ex vivo incubation with anti-CD5 monoclonal antibody-ricin immunotoxin (T101-R) for the purpose of graft-versus-host disease prophylaxis. Donor cell engraftment was documented in 28/29 patients by DNA restriction fragment length polymorphisms. In this pilot study the dose of T101-R incubated with donor marrow was increased in a stepwise manner from 300 ng (10 patients) to 600 ng (5 patients) to 1000 ng immunotoxin (IT)/10(7) bone marrow mononuclear cells (14 patients) in an attempt to achieve more effective GvHD prophylaxis. A statistically significant reduction in acute GvHD was achieved for patients receiving marrow pretreated with 1000 ng of immunotoxin (34%) compared to recipients of BM treated with 300 ng immunotoxin (100%, P = 0.0004). T-depleted marrow samples were evaluated for residual T cell activity using several in vitro assays including proliferation to the purified mitogen PHA (HA-17) and in mixed lymphocyte culture (MLC), T cell cytotoxicity, a limiting dilution assay for detecting precursors of proliferating T cells (LDApPTL), and phenotypic analysis of viable T cells expanded in 16-day culture with interleukin 2. The extent of T cell depletion determined by LDA assay varied widely at each immunotoxin concentration used. Thus, there was no correlation between the dose of T cells infused and subsequent GvHD. Phenotyping of lymphocytes recovered from immunotoxin-treated marrow demonstrated that residual T cells were CD5 negative in all cases tested. The only in vitro parameter that predicted subsequent acute or chronic GvHD was the demonstration of viable CD5 negative lymphocytes with T cell phenotype (CD2, CD3, and/or CD7 positive) after 16-day culture with IL-2 of the T-depleted bone marrow. We observed that such CD5 negative cells expressing other T cell markers have cytotoxic function and speculate that these cells may be capable of mediating GvHD in allogeneic transplantation.

Antigens, CD↗
PubMed1990

Identification of transfused blood cells in children with severe combined immunodeficiency syndrome by analysis of multiple cell lineages using restriction fragment length polymorphisms.

Four children with severe combined immunodeficiency syndrome (SCID) had evidence of circulating transfused cells detected by restriction fragment length polymorphism (RFLP). In two cases, the source of transfused cells was a single, unirradiated red cell transfusion and the patients developed severe graft-versus-host disease (GVHD). In another instance, engraftment of bone marrow cells, mononuclear cells, and neutrophils was noted 9 weeks following the infusion of 111indium-labeled maternal leukocytes for localization of infection. The patient also developed severe GVHD as a consequence of engraftment of functionally active maternal cells and rejected a paternal T cell-depleted marrow infused at a time when circulating maternal cells were present. In the fourth case, RFLP analysis was performed 2 h following completion of a leukocyte transfusion that had been irradiated with 3000 cGy prior to infusion. Third party mononuclear cells and neutrophils were transiently detected. The third party cells were of no clinical significance. The use of a limited panel of highly informative DNA probes allowed us to identify the affected circulating cell populations and source of foreign leukocytes in children with SCID without requiring a pretransfusion peripheral blood, bone marrow, or fibroblast sample.

Blood Transfusion↗
PubMed1989

Serum 5'nucleotidase and alkaline phosphatase--highly predictive liver function tests for the diagnosis of graft-versus-host disease in bone marrow transplant recipients.

The diagnostic efficacy of five serum liver function tests (aspartate and alanine aminotransferase, alkaline phosphatase, 5' nucleotidase, and bilirubin) was investigated in 95 bone marrow transplant recipients in whom acute graft-vs-host disease was graded by the Seattle criteria. The patient population included a control group of 22 autologous transplant recipients (group I), 33 patients with no GVHD (group II), 21 patients with grades 1 and 2 GVHD (group III), 12 patients with grade 3 GVHD (group IV), and 7 patients with grade 4 GVHD (group V). Student t test analysis of the analytes among the five groups of patients showed that 5' nucleotidase and alkaline phosphatase were the best discriminants among all the possible combinations of group pairs. Peak levels of 5' nucleotidase within each group of patients correlated well with those of alkaline phosphatase in all the allogeneic transplant groups (II-V; r = 0.59), but the correlation of these with bilirubin was less frequent. Also, 5' nucleotidase and alkaline phosphatase showed significant discrimination (P less than 0.05) even between groups I and II, suggesting that they are more sensitive than the Seattle criteria in the diagnosis of GVHD. They also showed the best overall discriminatory ability by one-factor analysis of variance (ANOVA; P = 0.0001 as compared with 0.002, 0.009, and 0.04 for aspartate aminotransferase, alanine aminotransferase, and bilirubin, respectively). Receiver-operating curves of the five analytes again revealed that 5' nucleotidase and alkaline phosphatase were by far the best discriminators among the five groups of patients. Bilirubin was relatively insensitive because it was a good discriminator only between the control group and groups IV and V. The hepatocellular enzymes, alanine and aspartate aminotransferase, correlated well (r = 0.80) but discriminated poorly among the four groups of allogeneic transplant recipients (II-V), suggesting that all four groups had some measure of hepatocellular damage that was independent of the severity of GVHD.

5'-Nucleotidase↗
PubMed1989

Prevention of graft rejection in allogeneic bone marrow transplantation: I. Preclinical studies with antithymocyte globulins.

Heterologous horse antithymocyte globulins (ATG) were investigated in vitro as potential immunotherapeutic reagents in the prevention of bone marrow graft rejection by allogeneic recipients. Different lots and concentrations of ATG were evaluated for their ability to inactivate natural killer (NK) cells, IL-2 cultured 'augmented' NK cells, and/or cytotoxic T cells (CTL) using the 51Cr-release assay for measurement of cytotoxic activity. In vitro incubation of peripheral blood mononuclear cells (PBMC) with a prototype non-myelotoxic ATG (ATGP12) at 0.1 mg/ml (a concentration which can be achieved with an i.v. infusion of approximately 30 mg ATG/kg daily) variously inhibited NK activity (0-100%); whereas treatment with the same concentration of ATGP12 and autologous human complement completely inhibited NK, as well as 'augmented' NK function from all normal individuals tested. Incubation of T cytotoxic effector cells with ATGP12 alone also significantly abrogated primed T cell cytotoxicity. These studies demonstrate that lots of ATG can be easily prescreened and titered in vitro in order to identify immunosuppressive reagents capable of inhibiting the MHC restricted and non-restricted cytotoxic cells, which can survive chemotherapy and radiation, and may play a critical role in resistance to engraftment of T cell-depleted marrow.

Antilymphocyte Serum↗
PubMed1988

Relationship of immunodeficiency to lymphoid malignancy.

Individuals with either primary or secondary immunodeficiencies are at high risk to develop not only infections but also malignancy (especially of the lymphoid system). The major focus of this paper is on malignancies that develop in immunodeficiency syndromes, particularly malignancies in naturally occurring immunodeficiencies and following bone marrow transplantation (BMT). As of August, 1986, 514 cases of naturally occurring immunodeficiencies have been registered at the Immunodeficiency Cancer Registry. Overall non-Hodgkin's lymphomas predominate in these patients, accounting for 48.6% of all cases. Non-Hodgkin's lymphoma is the predominant malignancy in ataxia-telangiectasia, common variable immunodeficiency, Wiskott-Aldrich syndrome (WAS) and severe combined immunodeficiency (SCID). The histopathology of the lymphomas differs somewhat in each of the disorders. In WAS, large cell "histiocytic" lymphoma predominates, with most cases having the features of B lymphocytes, including pleomorphic immunocytoma and immunoblastic lymphoma. Non-Hodgkin's lymphoma in SCID also generally has B cell features and in some cases multiple copies of Epstein-Barr virus (EBV) genomic DNA have been found in tumor tissue. In contrast to ataxia-telangiectasia, in which non-Hodgkin's lymphoma is also the predominant neoplasm, the morphology and cell marker characteristics are more similar to those seen in nonimmunodeficient children. The lymphomas in ataxia-telangiectasia are very heterogeneous with representation from all the major histologic subtypes. We have found no relationship between the degree of immunodeficiency and the development of malignancy. Immunodeficiency following BMT, as in naturally occurring immunodeficiencies, appears to predispose patients to the development of lymphoid malignancy, especially for recipients of partially mismatched bone marrow. In Minnesota 8 patients have developed B cell lympho-proliferative disorders (BLPD) following BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Ataxia Telangiectasia↗
PubMed1988

Conjugated hyperbilirubinemia and renal function in bone marrow transplant recipients.

Although it has long been recognized that hyperbilirubinemia is enhanced in patients with impaired renal function, a clear correlation between the levels of bilirubin and creatinine in serum has never been established. We have studied this relationship in 13 bone marrow transplant recipients who had episodes of combined conjugated hyperbilirubinemia and renal impairment. Most of the patients had graft-vs-host disease and various degrees of hepatic cholestasis as evidenced by histologic examination results and abnormal liver function tests. Serial serum specimens obtained during this period showed a good correlation between the two analytes, with a mean (+/- SD) correlation coefficient of .86 +/- .10. The slopes of the regression lines, represented as bilirubin-creatinine ratios, varied widely (0.2 to 3.6), reflecting the wide variation in the degree of hyperbilirubinemia attributable to renal impairment.

Adolescent↗
PubMed1987

Graft-versus-host disease prevention in allogeneic bone marrow transplantation from histocompatible siblings. A pilot study using immunotoxins for T cell depletion of donor bone marrow.

Seventeen patients, ages 7-53 years were transplanted with histocompatible bone marrow that had been depleted of T lymphocytes by ex vivo immunotoxin (IT) treatment. Twelve patients had high-risk acute leukemias, and five had chronic myelogenous leukemia. No other graft-vs.-host disease (GVHD) prophylaxis was used. A mixture of three anti-T-cell monoclonal antibodies conjugated to ricin were used in this study: TA-1, UCHT-1 (anti-CD3), and T101 (anti-CD5). The mean number of bone marrow cells infused was 1.5 X 10(8) mononuclear cells/kg recipient weight. Thirteen of the 17 patients demonstrated complete and sustained engraftment. Four patients experienced autologous marrow recovery and/or graft rejection. Compared with an historical group of leukemic patients who received GVHD prophylaxis with methotrexate alone or combinations of methotrexate, and prednisone plus antithymocyte globulin, (ATG) or OKT3, the IT patients with stable engraftment demonstrated shorter time to recovery of leukocytes greater than or equal to 1000mm3 for three consecutive days (median, 20 days vs. 26 days, P = .03). The recovery of total lymphocytes, B and T cell subsets, and T cell function by day 28 was highly variable, but similar, for patients in both the IT-treated group and historical controls. Four patients (ages 13, 18, 21, and 38) developed grade II skin GVHD, but none had severe GVHD. Eight of the 13 patients with durable engraftment have had posttransplant leukemic relapse. Currently only four patients remain alive; two have not relapsed posttransplant, while the other two achieved remission following posttransplant relapse. We conclude that severe GVHD was not observed in this small series with ex vivo T cell depletion for GVHD prophylaxis, and that favorable recovery of hematologic and lymphocytic function was demonstrated for cases where primary engraftment was sustained. A larger randomized controlled study will be needed to establish whether T cell depletion of donor bone marrow with IT can significantly reduce GVHD, and/or improve disease-free survival.

Adolescent↗
PubMed1987

The Immunodeficiency Cancer Registry. A research resource.

The Immunodeficiency Cancer Registry (ICR) contains nearly 500 case records regarding patients with primary immunodeficiencies who have developed malignancies. There is a proportional excess of lymphomas (50.7%) among the ICR cases and more than one-half of these cases were diagnosed at less than 10 years of age. Information in the ICR database is accessible to investigators conducting research on the biology or epidemiology of cancers associated with immunodeficiency.

Child↗
PubMed1987

Hodgkin's disease in pediatric patients with naturally occurring immunodeficiency.

A case/control study of pediatric patients with Hodgkin's disease (HD) was undertaken to compare clinical characteristics in patients with known underlying immunodeficiency (20 Immunodeficiency Cancer Registry cases) and without known immunodeficiency (100 Late Effects Study Group cases). Immunodeficiency Cancer Registry cases demonstrated a younger mean age at diagnosis (p = 0.03), and a significantly higher rate of failure to achieve remission (p = 0.001) than did the Late Effects Study Group controls. Also, Immunodeficiency Cancer Registry cases showed a proportional excess of unfavorable histologies when compared with large published pediatric series. These discrepancies are consistent with a common etiology of HD relating to underlying immune defect in Immunodeficiency Cancer Registry HD patients as well as HD patients (or a select subgroup) without known immunodeficiency disorders.

Adolescent↗
PubMed1987

B-cell lymphoproliferative disorders in children after bone marrow transplantation: radiologic manifestations.

The radiographic findings in five pediatric patients in whom unregulated B-cell lymphoproliferative disorders developed following bone marrow transplantation are described. Four patients received T-cell-depleted bone marrow from mismatched donors and one received nondepleted marrow from a matched sibling donor. These disorders are similar to B-cell lymphoproliferative disorders that have been described in other immunosuppressed hosts. They are associated with Epstein-Barr virus and range from polyclonal proliferation without cytogenetic abnormalities to monoclonal lymphoma with clonal cytogenetic changes. Unlike other postallograft lymphoproliferative processes, B-cell lymphoproliferative disorders in these patients have not responded to antiviral therapy, immunologic therapy, or chemotherapy. The radiographic patterns of disease include diffuse or focal hepatic involvement; gallbladder wall thickening; and pulmonary, soft-tissue, and basal-ganglion masses. These radiologic findings are not specific and evaluation of tissue histology is required for diagnosis.

Adolescent↗
PubMed1986

Cytogenetic studies in Wiskott-Aldrich syndrome: identification of a case with a 6p chromosome abnormality.

Lymphocytes from patients with Wiskott-Aldrich syndrome (WAS) were studied with prometaphase G banding to search for minor chromosome anomalies and in mutagen stress assays to assess the extent of chromosome breakage under these conditions. One patient, a sporadic case of WAS, was found to have a stable inversion of a large segment of one chromosome 6 that involved the region encoding the major histocompatibility complex (MHC). The anomaly was not present in the patient's parents, nor in three other unrelated patients with WAS, all of whom demonstrated X-linked inheritance (based on family history). None of the four patients showed an excessive number of breaks or radial exchange figures following exposure to mitomycin C or diepoxybutane. Thus chromosome fragility in WAS was not confirmed by these studies. However, the incidental finding of 6p inversion in a sporadic case of WAS suggests that genetic rearrangement involving the MHC can result in clinical immunodeficiency mimicking WAS.

Child, Preschool↗
PubMed1986

Progress in broadening the uses of marrow transplantation: donor availability.

The use of bone marrow transplantation as a curative treatment for congenital immunodeficiencies is limited by the lack of available histocompatible sibling donors. The problems associated with mismatched donor transplantation and efforts to overcome these difficulties are discussed, as are results obtained in transplantation with partially matched related and unrelated donors. The use of haploidentical relative donors, an attractive option due to the wider availability of such donors, is explored, along with the consequent need for T cell depletion. Methods of T cell depletion are compared, and efforts at improving depletion methods are discussed.

Agglutination Tests↗
PubMed1986

Successful donor cell engraftment in a recipient of bone marrow from a cadaveric donor.

A 12-year-old male with acute lymphocytic leukemia received donor bone marrow from his histocompatible father whose marrow was harvested 40 minutes postmortem after he suffered a myocardial infarction. The marrow was stored in liquid nitrogen for 17 days prior to infusion into the recipient. Trypan blue viability was greater than 99% for the fresh marrow. Progenitor cell assays revealed that 20% of the CFU-MIX, 16% of the BFU-E, 10% of the CFU-E, and 17% of the CFU-GM were spared during the cryopreservation period. Posttransplantation, the recipient had a leukocyte count greater than 10(3)/microL by day 26. Southern blotting analysis documented the donor origin of the peripheral blood mononuclear cells and granulocytes isolated 46 days posttransplantation. Unfortunately, the patient died of complications relating to graft-v-host disease 67 days following transplantation. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells and is the first reported case of documented leukocyte engraftment in a recipient of cadaveric marrow.

Bone Marrow Transplantation↗