A history of surgical suction from Dieulafoy to Gomco.
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Equipment Design↗
Biomedical subjects
M D Pescovitz
Publications and source records attributed to M D Pescovitz.
Bone marrow transplantation in miniature swine. I. Development of the model.
Procedures for successful autologous and MHC-matched allogeneic bone marrow transplantation in partially inbred, MHC-defined miniature swine have been established. All marrow recipients were conditioned with single-dose total-body irradiation at the upper level of tolerance, and supported with antibiotics and irradiated blood products during aplasia. Surgical harvest of autologous and allogeneic marrow yielded sufficient numbers of cells to successfully reconstitute recipients. Radiation control animals that received no marrow failed to show recovery of marrow function. Pigs transplanted with autologous marrow at doses greater than 10(8) cells/kg routinely engrafted and recovered normal marrow function. The major clinical complications were acute and chronic infections and hemorrhage. T cell-depleted autologous marrow also engrafted, and there was no observed increase in clinical complications. In bone marrow transplantation across non-MHC allogeneic differences, engraftment and survival were similar to that observed for autologous transplants. The T cell depletion of marrow in such MHC-matched allogeneic recipients was associated in one animal, however, with early reconstitution by cells of autologous origin.
Animals↗
Bone marrow transplantation in miniature swine. II. Effect of selective genetic differences on marrow engraftment and recipient survival.
In order to study the effect of defined genetic differences on bone marrow transplantation in miniature swine, five different combinations of major histocompatibility complex (MHC)-matched and mismatched bone marrow transplants were performed. Eight of nine fully MHC-mismatched allogeneic bone marrow transplants failed to reconstitute, and one animal reconstituted briefly but then died quickly thereafter. Five of six class I-matched/class II-mismatched (g----c) bone marrow transplants engrafted, showed a skin rash typical of graft-versus-host (GVH) reaction, and died 3 weeks after the marrow transplantation. None of five class II-matched/class I-mismatched (g----d) transplants engrafted. Parental marrow transplants into F1 hosts engrafted and caused GVH skin rash, with survivals from 1 to 9 months (n = 5). Serologic typing of the F1 recipients of parental marrow showed only donor-type peripheral blood lymphocytes (PBL), suggesting complete marrow replacement. Conversely, F1 into parental marrow transplants showed no engraftment (n = 6). These results indicate that resistance to MHC-mismatched allogeneic bone marrow engraftment in swine represents a host response recognizing donor class I MHC differences. This response appears to interfere with engraftment of donor bone marrow cells despite host preparation with 900-1100 rads total-body irradiation. In the absence of donor MHC class I differences, engraftment was seen despite the existence of multiple non-MHC differences, and even in the presence of class II differences. Such engraftment also led to GVH, varying in intensity according to the strength of genetic disparity (i.e., worst in parent----F1 combination). These results suggest that miniature swine should provide an effective model for study of both GVH elimination (in the parent----F1 combination) and problems of engraftment (in the F1----parent combination), the two most important obstacles to clinical allogeneic transplantation.
Animals↗
Expression of T-cell associated antigens by porcine natural killer cells.
We have examined the cell surface phenotype of porcine natural killer (NK) cells and compared them with classic porcine cytotoxic T lymphocytes (CTL). NK cells were susceptible to treatment with monoclonal antibodies to CD2 (PT11), CD8 (PT8) and Ia plus complement (C), as well as with antiserum to asialo-GM1 (ASGM1) plus C. In addition, monoclonal antibodies to leucocyte function antigen 1 (LFA-1) but not to CD8 blocked NK-mediated lysis in the absence of C. This is in contrast to porcine CTL, which were eliminated by antibodies to CD2, CD8 and Ia plus C, but not by anti-ASGMI plus C, and which were blocked by anti-CD8 in the absence of C. Therefore, although porcine NK cells are similar to porcine CTL, they are distinguished by several important differences.
Animals↗
Bone marrow transplantation in miniature swine. III. Graft-versus-host disease and the effect of T cell depletion of marrow.
Graft-versus-host disease (GVHD) has been evaluated in partially inbred miniature swine in order to study this complication of allogeneic bone marrow transplantation (BMT) in a major histocompatibility complex (MHC) genetically defined large animal model. Bone marrow from MHC homozygous ("parental") swine was injected into irradiated (900 rads total-body irradiation) MHC heterozygous ("F1") swine that shared one haplotype with the donor. All 18 animals successfully engrafted with donor bone marrow, and 17 of these developed skin rash of varying intensity depending on the extent of T cell depletion of infused marrow. Of 18 animals, 8 received undepleted bone marrow from exsanguinated donors and 2 also received additional peripheral blood lymphocytes (PBL) as a source of mature T cells. All 8 showed a moderate-to-severe rash, and the 2 pigs that received additional donor PBL developed the most severe rash. The cutaneous eruption seen in this model clinically, histologically, and immunologically resembled human GVHD. Two protocols of T cell depletion of donor bone marrow by antiporcine T cell monoclonal antibodies plus complement were tested for their effect on development of GVHD. The combination of two monoclonal antibodies, 74-12-4 (PT4) and 76-2-11 (PT8), had a marginal effect on the subsequent development of cutaneous manifestations of GVHD. However, treatment of the donor marrow by a combination of three monoclonal antibodies--PT4, PT8, and MSA4 (PT11)--effectively decreased the severity of the GVHD skin rash. These results indicate that (1) the GVHD associated with allogeneic bone marrow transplantation in swine is dependent on T cells in the marrow; (2) effective T cell depletion of donor marrow by monoclonal antibodies and complement does not prevent engraftment; and (3) this swine GVHD model, which allows study with F1 and homozygous parental combinations in an MHC genetically defined large animal, is particularly useful for the understanding of GVHD pathogenesis, prevention, and treatment.
Animals↗
Tissue-specific expression and structure of a divergent member of a class I MHC gene family.
The class I gene family of the major histocompatibility complex (MHC) of the miniature swine (SLA) contains seven members. Six of these are highly homologous, whereas the seventh, PD6, is only distantly related. A genomic clone containing PD6 has been isolated and characterized. The PD6 SLA gene, although only 55% homologous to the other SLA class I sequences, is still a member of the family; its size and exon/intron organization are similar to other class I genes. When aligned with other SLA genes, exons 1 to 6 of PD6 have open reading frames; exon 7 contains a termination codon. PD6 is transcribed in transfected mouse L cells where its expression is enhanced by interferon. In vivo expression of PD6 is observed in a variety of tissues, with the highest levels in mature lymphoid tissues. Peripheral T cells contain high levels of PD6-specific RNA relative to B cells, whereas no PD6 transcripts are detectable in thymocytes.
Amino Acid Sequence↗
Cytotoxic T lymphocyte recognition of a xenogeneic major histocompatibility complex antigen expressed in transgenic mice.
Introduction of a porcine major histocompatability complex (MHC) class I gene (PD1) into the genome of a C57BL/10 (B10) mouse has been shown to lead to cell surface expression of the porcine MHC antigen, SLAPD1 in a transgenic mouse. The PD1 product expressed on spleen cells from the transgenic mice stimulated B10 spleen cells in a mixed lymphocyte culture to generate PD1-specific cytotoxic T lymphocytes (CTL). The CTL were PD1 specific since they lysed transgenic splenic blast cells and PD1-transfected L cells, but not B10 blasts or control L cells. The CTL were L3T4-, Lyt-2+ and their activity was partially inhibited by either anti-Lyt-2 antibody or by anti-swine MHC alloantibodies. The repertoire of responding B10 anti-transgenic CTL was assessed by examining their cross-reactivity on a series of murine allogeneic targets. The B10 anti-transgenic CTL showed some cross-reactivity on conventional allogeneic targets, but reacted strongly on a series of mutant H-2Kbm blast cells. In addition, B10 anti-B6.cH-2bm6 CTL cross-reacted extensively on the transgenic target cells. These results demonstrated that normal B10 CTL possess a repertoire specific for the products of the xenogeneic class I gene PD1, that this repertoire is cross-reactive with the conventional alloreactive CTL repertoire, and that there exists an unanticipated relationship between PD1-specific CTL and CTL specific for Kb mutant determinants.
Animals↗
Phenotypic and functional characterization of pig lymphocyte populations.
Monoclonal antibodies reactive with swine lymphoid cell subpopulation antigens and with the swine major histocompatibility complex, the SLA complex, antigens are summarized. The mAb have been used to analyze swine peripheral T cell populations, the CD4+ helper T cells and the CD8+ cytotoxic/suppressor T cells. Three unique properties of swine T cells have been described. 1) There is an unusually high (25%) number of CD4+ CD8+ dual expressor T cells. 2) The ratio of CD4+ to CD8+ T cells is lower than expected; the ratio of 0.6, which is normal for pigs, only occurs in pathological conditions in humans. 3) Resting CD8+ cells preferentially express class II SLA antigens. The significance of these unusual properties of swine T cells is currently under study.
Animals↗
Thromboembolic complications in renal allograft recipients. A report from the prospective randomized study of cyclosporine versus azathioprine-antilymphocyte globulin.
The incidence of arterial and venous thromboembolic complications was compared in 224 renal allograft recipients who were prospectively randomized and stratified by risk to treatment with either cyclosporine-prednisone (CsA-P) (n = 117) or azathioprine-prednisone-antilymphocyte globulin (AZA-P-ALG) (n = 107). Thirteen CsA patients (11%) had 22 thromboembolic events, while 19 AZA patients (18%) had 24 events (P = 0.22). There was no significant difference between the 2 regimens in the number of patients with each type of venous or arterial event or in the number of patients with multiple or lethal events. The incidence of "minor" complications (all except myocardial infarction and stroke) in the related donor subgroup (n = 85) and the overall incidence of thromboembolism in the diabetic subgroup (n = 125) were both significantly higher in AZA-treated patients (P = 0.008 and 0.045, respectively). Thus, CsA immunosuppression does not appear to be a risk factor for thromboembolic disease, and it may in fact lower the incidence of thromboembolism in diabetic renal allograft recipients.
Adolescent↗
Frequency of diabetes-related complications in renal allograft recipients prospectively randomized to cyclosporine or azathioprine.
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Azathioprine↗
Production of monoclonal antibodies against human growth hormone releasing hormone and their use in an enzyme-linked immunosorbent assay (ELISA)
Two murine monoclonal antibodies (mAbs) specific for human growth hormone releasing hormone (GHRH-44-NH2) were produced from a fusion of spleen cells from a BALB/c mouse immunized with GHRH-conjugated BSA with SP 2/0 myeloma cells. The antibodies were of the IgG1 kappa, and IgG2b-kappa isotypes. The binding of both antibodies to GHRH-coated plates was inhibited by a 30-44 amino acid fragment but not by a 1-26 fragment. Thus, both antibodies are directed against the carboxy terminus of the peptide. Furthermore, both antibodies bind to the same epitope on the 30-44 amino acid portion since they cross-inhibit each other's binding to intact GHRH. Using these mAbs, a direct binding GHRH enzyme-linked immunosorbent assay (ELISA) was developed which had a least detectable dose of 30 pg. The availability of these antibodies and their use in ELISA methodology permits consistent and specific detection of GHRH in a non-isotope assay. They should prove of value in screening acromegalic patients for ectopic sources of GHRH secretion and in studies of ontogenic analysis of GHRH production.
Animals↗
Monoclonal antibodies against SU-DHL-1 cells stain the neoplastic cells in true histiocytic lymphoma, malignant histiocytosis, and Hodgkin's disease.
Three murine monoclonal antibodies, named 2H9, 1E9 and 1A2, were produced after immunization of BALB/c mice with cells of the SU-DHL-1 cell line from a true histiocytic lymphoma. In frozen sections from various lymphomas, 2H9 and 1A2 selectively stained the cell membranes of neoplastic cells in true histiocytic lymphoma and Hodgkin's disease. Antibody 1E9 stained the nuclear membranes of the tumor cells in true histiocytic lymphoma and malignant histiocytosis. No staining was seen in 56 cases of B and T cell lymphoma. Several tissue culture cell lines, including T cell acute lymphoblastic leukemia and pre-B cell lines, were not stained. With 2H9, however, a positive reaction was noted for two Epstein-Barr virus (EBV)-positive African Burkitt's lymphoma cell lines (Daudi and P3HRI), one human T cell lymphoma/leukemia-virus-positive cell line (HUT 102), and one EBV-transformed normal B lymphoblastoid cell line (RPMI 8057). In normal lymphoid tissues, 2H9 and 1E9 reacted with the nuclear membranes of histiocytes and interdigitating reticulum cells, whereas 1A2 stained only rare cells of an unknown type. All three antibodies failed to react with B or T cells in frozen tissue sections of normal lymphoid tissues. The use of these three antibodies should facilitate the diagnosis of histiocyte and interdigitating reticulum (IR) cell-related neoplasms, namely, true histiocytic lymphoma, malignant histiocytosis, and Hodgkin's disease. True histiocytic lymphoma and Hodgkin's disease exhibit similar reactivities with these three and with two other monoclonal antibodies (HeFi-1 and Tac), suggesting that these two types of lymphoma are related. In contrast, malignant histiocytosis was negative for 2H9, 1A2, Tac, and HeFi-1. The difference in the phenotypic expression of true histiocytic lymphoma and malignant histiocytosis indicates that they are two different disease entities.
Animals↗
Anti-idiotype to monoclonal anti-swine SLA antibody detects a common idiotype shared by mouse anti-SLA sera and elicits an anti-SLA activity.
Heterologous anti-idiotypic reagents have been prepared against a BALB/c anti-swine MHC (SLAd) monoclonal antibody (74-11-10) in order to test for possible interspecies idiotypic cross-reactions of anti-MHC antibodies. Using these reagents to examine xenoantisera produced in BALB/c mice immunized with swine SLAdd peripheral blood lymphocytes, all animals tested were found to express detectable levels of the 74-11-10 idiotype (Id). The Id could also be detected in one out of five BALB/c mice immunized with swine SLAcc PBL. Swine anti-SLAdd alloantibodies were also tested, but failed to show detectable levels of the 74-11-10 Id. The in vivo administration of anti-idiotypic reagents to BALB/c mice induced detectable levels of 74-11-10 Id positive antibodies that bound specifically to SLAdd PBL. Similar treatment of SLAgg swine (recombinant swine expressing the class I MHC molecules of c) with anti-idiotypic antibodies failed to induce anti-SLAd antibody activity. These results thus indicate that 74-11-10 represents a shared idiotype of BALB/c anti-SLAdd antibodies. The presence of 74-11-10 Id in one mouse immunized with SLAcc PBL suggests that the failure of pigs to express the 74-11-10 Id following treatment with anti-idiotypic antibodies may be the result of tolerance rather than absence of the relevant variable region gene(s).
Animals↗
Murine anti-swine T4 and T8 monoclonal antibodies: distribution and effects on proliferative and cytotoxic T cells.
Two murine monoclonal antibodies reactive with porcine nylon wool-nonadherent T cells were examined by flow microfluorometry analysis for cellular distribution, and by functional analysis for their effect on MLR and CTL assays. The two determinants recognized, called PT4 and PT8, were shown to be expressed on almost mutually exclusive cell populations, with only 6 to 15% of T cells expressing both antigens. Among the 15% of nylon wool-nonadherent cells that did not express either PT4 or PT8, 5% were surface Ig+. In functional assays, cells that proliferated to PHA, hen egg lysozyme, and alloantigens were blocked by PT4 and were eliminated by PT4 and complement. PT4 and complement had no effect on CTL effectors or precursors. Reciprocally, PT8 blocked and PT8 and complement eliminated CTL effectors and precursors, but had no effect on proliferative responses. These results indicate that PT4 and PT8 define the porcine helper and cytotoxic T cell subsets, respectively.
Animals↗
Effect of class II antigen matching on renal allograft survival in miniature swine.
The benefit of class II major histocompatibility complex (MHC) antigen matching to renal allograft survival, in the absence of immunosuppression, has been studied in partially inbred miniature swine. Permanent (greater than 6 mo) renal allograft survival was found in 30% of recipients of either class II only or fully matched grafts. Analysis of the survival of the class II-only matched grafts by specific recipient/donor haplotype combinations indicated that survival was regulated by at least three genetic factors, including antigen gene dose, a class I MHC allele-dependent effect, and non-MHC-linked immune response phenomenon. Animals accepting class II-matched kidneys developed spontaneous tolerance to the graft, despite mounting an initial immune response marked by renal damage and the development of serum cytotoxic antibodies directed at the donor MHC antigens. The antibodies were only of the IgM class, suggesting that conversion of the humoral response to IgG was blocked. After acceptance of the kidney, three out of five animals showed specific prolongation of donor skin grafts. At the time of rejection of these skin grafts, no decrease in renal function nor reappearance of anti-donor antibodies was observed.
Animals↗
Umbilical hernia repair in patients with cirrhosis. No evidence for increased incidence of variceal bleeding.
Umbilical hernias are common in patients with alcoholic cirrhosis. Often elective repair is delayed for fear of precipitating acute variceal bleeding by interruption of portal--systemic venous collaterals. In order to test this hypothesis, the incidence of variceal bleeding following repair of umbilical hernia was determined retrospectively in 22 consecutive patients from our hospital and 74 others from six reports in the literature. Overall the perioperative (less than 3 months postrepair) incidence of variceal bleeding was 11%. This incidence of bleeding was equal to the incidence of bleeding reported in the literature in a group of cirrhotics with varices who did not undergo surgery. In addition, no correlation was seen between patients with a preoperative history of varices or bleeding and those who bled after surgery. Therefore, surgical repair of umbilical hernia can be performed in these patients without additional risk of precipitating variceal bleeding.
Adult↗
Immunologic characterization of MHC recombinant swine: role of class I and II antigens in in vitro immune responses.
A recombinant haplotype between the class I and class II major histocompatibility loci of inbred miniature swine has made it possible to study the role of the corresponding antigens in in vitro and in vivo immune responses. Before examining the effects of selective SLA locus matching on allograft survival, it was deemed necessary to determine the corresponding effects on in vitro parameters of immunity. The results presented in this paper indicate that: (1) a difference at the class II loci was required for a maximal proliferative response; (2) class I antigen differences alone led to a slight proliferative response which depended on the haplotype combination used; (3) in cell-mediated cytoxicity assays, the class I antigens were found to be the primary targets for lysis. Although optimal CTL generation required the presence of both class I and class II antigen differences, CTL were sometimes generated in the absence of a known class II difference. The weak, intermittent cytotoxicity seen in these cultures of class II matched cells could be augmented by the addition of third party, class I matched, class II mismatched, stimulator cells. Taken together, these data provide evidence for the conservation of function of antigen class between species. They also provide further evidence for the two-signal hypothesis of CTL generation. Thus, MHC recombinant swine provide a model for the study of the effect of antigen class on in vitro and in vivo immunobiology.
Animals↗
Localization of class II MHC antigens on porcine renal vascular endothelium.
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Animals↗