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Biomedical subjects

M Basker

Publications and source records attributed to M Basker.

At least 19 recordsLinked to original sources
PubMed2000

Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates.

BACKGROUND: Efforts to achieve tolerance to transplanted pig organs in nonhuman primates by the induction of a state of mixed hematopoietic chimerism have been associated with disorders of coagulation and thrombosis. Activation of recipient vascular endothelium and platelets by porcine hematopoietic cells and/or activation of donor organ vascular endothelium and/or molecular differences between the species may play roles. Irradiation or drug therapy could possibly potentiate endothelial cell activation and/or injury. METHODS: We have investigated parameters of coagulation and platelet activation in nonhuman primates after (1) a regimen aimed at inducing mixed hematopoietic chimerism and tolerance (TIR that included total body irradiation, T cell depletion, and splenectomy; (2) pig bone marrow or pig peripheral blood mobilized progenitor cell transplantation (PCTx); and/or (3) pig organ transplantation (POTx). Five experimental groups were studied. Baboons were the recipient subjects in all groups except Group 1. Gp 1 Cynomolgus monkeys (n=6) underwent TIR + allotransplantation of hematopoietic cells and a kidney or heart or TIR + concordant xenotransplantation (using baboons as donors) of cells and a kidney; Gp 2 Baboons (n=4) underwent TIR with or without (+/-) autologous hematopoietic cell infusion; Gp 3 (n=12) PCTx+/-TIR; Gp 4 (n=5) POTx+/-TIR; Gp 5 (n=4) TIR + PCTx + POTx. Platelet counts, with plasma prothrombin time, partial thromboplastin time, fibrinogen levels, fibrin split products and/or D-dimer were measured. RESULTS: In the absence of a discordant (porcine) cellular or organ transplant (Groups 1 and 2), TIR resulted in transient thrombocytopenia only, in keeping with bone marrow depression from irradiation. PCTx alone (Group 3) was associated with the rapid development of a thrombotic thrombocytopenic (TTP)-like microangiopathic state, that persisted longer when PCTx was combined with TIR. POTx (+/-TIR) (Group 4) was associated with a gradual fall (over several days) in platelet counts and fibrinogen with disseminated intravascular coagulation (DIC); after graft excision, the DIC generally resolved. When TIR, PCTx and POTx were combined (Group 5), an initial TTP-like state was superseded by a consumptive picture of DIC within the first week, necessitating graft removal. CONCLUSIONS: Both PCTx and POTx lead to profound alterations in hemostasis and coagulation parameters that must be overcome if discordant xenotransplantation of hematopoietic cells and organs is to be fully successful. Disordered thromboregulation could exacerbate vascular damage and potentiate activation of coagulation pathways after exposure to xenogeneic cells or a vascularized xenograft.

Animals↗
PubMed2000

High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response.

BACKGROUND: In pig-to-primate organ transplantation, hyperacute rejection can be prevented, but the organ is rejected within days by acute vascular rejection, in which induced high-affinity anti-Gal alpha1-3Gal (alphaGal) IgG and possibly antibodies directed against new porcine (non-alphaGal) antigenic determinants are considered to play a major role. We have explored the role of an anti-CD40L monoclonal antibody in modifying the humoral response to porcine hematopoietic cells in baboons pretreated with a nonmyeloablative regimen. METHODS: Porcine peripheral blood mobilized progenitor cells obtained by leukapheresis from both major histocompatibility complex-inbred miniature swine (n=7) and human decay-accelerating factor pigs (n=3) were transplanted into baboons. Group 1 baboons (n=3) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with ATG, complement depletion with cobra venom factor, short courses of cyclosporine, mycophenolate mofetil, porcine hematopoietic growth factors, and anti-alphaGal antibody depletion by immunoadsorption before transplantation of high doses (2-4 x 10(10)/cells/kg) of peripheral blood mobilized progenitor cells. In group 2 (n=5), cyclosporine was replaced by eight doses of anti-CD40L monoclonal antibodies over 14 days. The group 3 baboons (n=2) received the group 1 regimen plus 2 doses of anti-CD40L monoclonal antibodies (on days 0 and 2). RESULTS: In group 1, sensitization to alphaGal (with increases in IgM and IgG of 3- to 6-fold and 100-fold, respectively) and the development of antibodies to new non-alphaGal porcine antigens occurred within 20 days. In group 2, no sensitization to alphaGal or non-alphaGal determinants was seen, but alphaGal-reactive antibodies did return to their pre- peripheral blood mobilized progenitor cells transplant levels. In group 3, attenuated sensitization to alphaGal antigens was seen after cessation of cyclosporine and mycophenolate mofetil therapy at 30 days (IgM 4-fold, IgG 8-30-fold), but no antibodies developed against new porcine determinants. In no baboon did anti-CD40L monoclonal antibodies prevent sensitization to its own murine antigens. CONCLUSIONS: We believe these studies are the first to consistently demonstrate prevention of a secondary humoral response after cell or organ transplantation in a pig-to-primate model. The development of sensitization to the murine elements of the anti-CD40L monoclonal antibodies suggests that nonresponsiveness to cell membrane-bound antigen (e.g., alphaGal) is a specific phenomenon and not a general manifestation of immunological unresponsiveness. T cell costimulatory blockade may facilitate induction of mixed hematopoietic chimerism and, consequently, of tolerance to pig organs and tissues.

Animals↗
PubMed2000

Plasma perfusion by apheresis through a Gal immunoaffinity column successfully depletes anti-Gal antibody: experience with 320 aphereses in baboons.

BACKGROUND: Anti-Galalpha1-3Gal (Gal) antibodies (Gal Ab) contribute to the rejection of porcine organs transplanted into primates. Extracorporeal immunoadsorption (EIA) has been developed to eliminate Gal Ab from the circulation. METHODS: Between 1995 and 1999 we performed 320 EIAs in baboons using a COBE-Spectra apheresis unit incorporating a synthetic Gal immunoaffinity column. Three plasma volumes were immunoadsorbed on each occasion. The 221 consecutive EIAs performed in 41 immunosuppressed baboons between January 1997 and April 1999 form the basis of this review. Of these 41 baboons, 29 underwent a series of three or four EIAs at daily intervals, seven had multiple series of three EIAs, and the remainder underwent single or double EIAs. Serum Gal Ab levels were monitored by ELISA before and at intervals after the course of EIA. RESULTS: There were two fatal complications, one from a respiratory mishap (unrelated to the EIA) and one from persistent hypotension unresponsive to therapeutic interventions. Seven procedures (3%) were terminated early owing to technical difficulties and/or persistent hypotension. Mean pre-EIA Gal Ab levels in naive baboons were 33.1 microg/ml (IgM) and 14.5 microg/ml (IgG). Immediately after three consecutive EIAs, IgM was depleted by a mean of 97.3% and IgG by 99.4%. By 18 to 24 h later, Gal Ab was returning but depletion remained at 80.1% (IgM) and 84.7% (IgG). The subsequent rate of return of Gal Ab depended on the immunomodulatory protocol used. CONCLUSIONS: (1) With appropriate monitoring, EIA is an acceptably safe procedure, even in small (<10 kg) baboons. (2) Three consecutive EIAs are effective in removing >97% of Gal Ab. (3) In the majority of cases, return of Gal Ab begins within 24 h, irrespective of the immunomodulatory protocol.

Animals↗
PubMed2000

Decreased graft-versus-host disease after haplotype mismatched bone marrow allografts in miniature swine following interleukin-2 treatment.

Graft-versus-host disease (GVHD) is an important complication of bone marrow transplantation after transplants between HLA-mismatched donor/recipient pairs. In mice, giving IL-2 post transplant decreases GVHD in this setting. We studied high-dose IL-2 therapy in pigs. Transplants were carried out after conditioning with fractionated total body radiation and cyclophosphamide. Fourteen pigs received a fully mismatched bone marrow transplant (six with IL-2; eight without IL-2), and six received a single haplotype class II mismatched transplant (three with IL-2; three without IL-2). GVHD was evaluated by skin histology. All fully mismatched recipients had severe GVHD (grade 2-3) and died within 13 to 51 days whether or not they received IL-2. Pigs receiving a one haplotype class II mismatched transplant without IL-2 developed severe skin GVHD lasting for 8-45 days; all died within 57 days. Similar pigs receiving IL-2 post transplant had no or only mild skin GVHD for less than 15 days; two are long-term survivors. Bone Marrow Transplantation (2000) 25, 47-52.

Animals↗
PubMed2000

Pharmacotherapeutic agents in xenotransplantation.

The ability to transplant pig organs into humans would resolve the current crisis in the supply of cadaveric human organs for the treatment of end stage disease. Several immunologic barriers need to be overcome if pig-to-primate transplantation is to be successful. The presence of preformed antibodies in humans, apes and Old World monkeys directed against galactose epitopes on pig vascular endothelium provides the major barrier, as binding of antibody to antigen leads to graft destruction by complement activation and other mechanisms. Hyperacute rejection can result from the action of complement. If this is prevented, delayed antibody-mediated rejection develops, which can be associated with a state of consumptive coagulopathy (disseminated intravascular coagulation, DIC). Efforts being made to overcome antibody-mediated rejection include depletion of antibody by extracorporeal immunoadsorption, prevention of an induced antibody response by co-stimulatory blockade, B-cell and/or plasma cell depletion, depletion or inhibition of complement, or the use of organs from pigs transgenic for a human complement regulatory protein, such as hDAF. The ultimate solution would be the induction of both B- and T-cell tolerance to the transplanted pig organ, which is being explored by attempting to induce haematopoietic cell chimerism. One complication of this is a thrombotic microangiopathy, similar to thrombotic thrombocytopenic purpura. The many and diverse roles in which pharmacotherapy is involved in attempts to overcome the barriers of xenotransplantation are reviewed and current progress, particularly in our own laboratory, is discussed.

Animals↗
PubMed1999

The problem of anti-pig antibodies in pig-to-primate xenografting: current and novel methods of depletion and/or suppression of production of anti-pig antibodies.

The role of antibodies directed against Galalpha1-3Gal (alpha-Gal) epitopes in porcine-to-primate xenotransplantation has been widely studied during the past few years. These antibodies (anti-alpha-Gal) have been associated with both hyperacute rejection and acute vascular rejection of vascularized organs. Depletion and (temporary or permanent) suppression of production of anti-alpha-Gal seem to be essential to the long-term survival of these organs, even when the ultimate aim is accommodation or tolerance. Although more than 95% depletion of anti-alpha-Gal can be achieved by the use of immunoaffinity column technology, to date no regimen has been successful in preventing the return of anti-alpha-Gal (from continuing production). In this review, we discuss current and novel methods for achieving depletion or inhibition (i.e. extracorporeal immunoadsorption, anti-idiotypic antibodies, the intravenous infusion of immunoglobulin or oligosaccharides) and suppression of production (i.e. irradiation, pharmacologic agents, specific monoclonal antibodies, immunotoxins) of anti-alpha-Gal antibodies.

Animals↗
PubMed1999

Peripheral blood progenitor cell mobilization and leukapheresis in pigs.

BACKGROUND AND PURPOSE: The pig is being investigated as an organ donor for humans. Induction of immunologic tolerance to pig tissues in primates would overcome the major immunologic barriers to xenotransplantation. A proven method of inducing tolerance to allografts is by the induction of mixed hematopoietic chimerism by bone marrow transplantation. We are therefore investigating induction of mixed hematopoietic chimerism in the pig-to-baboon model. METHODS: To obtain large numbers of pig hematopoietic cells, leukapheresis was used to collect blood cell products in miniature swine (n = 5) after progenitor cell mobilization by use of a course of hematopoietic growth factors (cytokines), consisting of porcine interleukin 3, porcine stem cell factor, and human granulocyte colony-stimulating factor. RESULTS: Cytokine therapy and leukapheresis were well tolerated. Cytokine therapy increased the total white blood cell count and allowed large numbers of leukocytes (60 x 10(10)) to be obtained by apheresis, of which approximately 0.1% were granulocyte-erythrocyte-monocyte-megakaryocyte colony-forming units (CFU-GEMMs), which are considered to be representative of hematopoietic progenitors with multi-lineage potential. CONCLUSIONS: The combination of cytokine therapy and leukapheresis enables hematopoietic progenitor cells to be obtained safely from miniature swine.

Animals↗
PubMed1991

The diffusion of beta-lactam antibiotics through mixed gels of cystic fibrosis-derived mucin and Pseudomonas aeruginosa alginate.

The rates of diffusion through purified extracellular alginate from Pseudomonas aeruginosa were measured for twelve beta-lactam antibiotics. The diffusion rate was reduced as the antibiotic molecular weight increased, but the range of diffusion rates exhibited by a common anti-pseudomonal penicillins was relatively small. The diffusion of ticarcillin through 1.0% w/v mixtures of alginate and purified mucus glycoprotein (mucin) from sputa of cystic fibrosis patients showed that, at equivalent concentrations, alginate represented the greater barrier to penetration. However if the mucin concentration was increased to 4.0% w/v, a more realistic physiological concentration, the diffusion of ticarcillin was retarded to a greater extent than in 1% w/v alginate, and the effect was compounded by other sputum components such as DNA. The results suggest that the antibiotic diffusion barrier represented by mucin may be significant in vitro, particularly for nebulized antibiotics.

Alginates↗
PubMed1983

Adenotonsillectomies on a surgical day-clinic basis.

Adenotonsillectomies are a common surgical procedure. A review is given of 892 cases of tonsillectomies and adenoidectomies performed on a basis of short hospitalization without added risk. Benefits, both financial and psychological, are described.

Adenoidectomy↗