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J L Platt

Publications and source records attributed to J L Platt.

At least 109 records · Page 6Linked to original sources
PubMed1997

Recent advances in the immunology of xenotransplantation.

The transplantation of tissue and organs between individuals of different species, that is xenotransplantation, engenders a variety of severe immune responses. Xenogeneic immune responses mediated by naturally occurring antibodies and complement lead to hyperacute and acute vascular rejection of vascularized organ grafts and may also cause vascular rejection of cell and tissue grafts. Under some circumstances, however, a vascularized organ graft may evade humoral rejection despite the presence of antidonor antibodies in the circulation of the recipient; this condition is called accommodation. Xenogeneic immune responses mediated by T-lymphocytes and natural killer cells may cause acute cellular rejection. The extent to which cellular rejection of xenografts resembles cellular rejection of allografts remains to be determined. New insights into the molecular mechanisms underlying the immune responses to xenotransplantation have shed new light on the pathogenesis of immunological disease and have allowed the development of specific immunomodulatory strategies that may facilitate clinical application of xenotransplantation.

Animals↗
PubMed1997

Swine lungs expressing human complement-regulatory proteins are protected against acute pulmonary dysfunction in a human plasma perfusion model.

UNLABELLED: Pulmonary transplantation is currently limited by the number of suitable cadaver donor lungs. For this reason, pulmonary xenotransplantation is currently being investigated. OBJECTIVE: Our goal was to assess the role of complement in pulmonary xenograft dysfunction. METHODS: The pulmonary function of swine expressing human decay accelerating factor and human CD59 (n = 6) was compared with that of the lungs from nontransgenic (control) swine (n = 6) during perfusion with human plasma. RESULTS: After 2 hours of perfusion, the pulmonary vascular resistance was 1624 +/- 408 dynes.sec.cm-5 in control lungs and 908 +/- 68 dynes.sec.cm-5 in transgenic lungs (p < 0.05). Control lungs had a venous oxygen tension of 271 +/- 23 mm Hg with a ratio of venous oxygen tension to inspired oxygen fraction of 452 +/- 38 at 2 hours of perfusion; transgenic lungs had a venous oxygen tension of 398 +/- 11 mm Hg and a ratio of venous oxygen tension to inspired oxygen fraction of 663 +/- 18 (p < 0.05). Control lungs showed a decrease of 79.8% +/- 3.7% in static pulmonary compliance by 2 hours, versus a 12.0% +/- 8.1% decrease by the transgenic lungs (p < 0.05). The control lungs also developed 561.7 +/- 196.2 ml of airway edema over 2 hours, in contrast to 6.5 +/- 1.7 ml in transgenic lungs (p < 0.05). CONCLUSION: Lungs from swine expressing human decay accelerating factor and human CD59 functioned better than nontransgenic swine lungs when perfused with human plasma. These results suggest that complement activation is involved in producing acute pulmonary xenograft dysfunction and demonstrate that lungs from swine expressing human decay accelerating factor and human CD59 are protected against pulmonary injury when perfused with human plasma.

Animals↗
PubMed1997

Humoral responses to pig-to-baboon cardiac transplantation: implications for the pathogenesis and treatment of acute vascular rejection and for accommodation.

Organs transplanted between phylogenetically-disparate species, such as from the pig into the primate, are subject to hyperacute and acute vascular rejection. Hyperacute rejection of a porcine organ by a primate is thought to be initiated by the binding of xenoreactive natural antibodies to Galalpha1-3Gal expressed on the endothelial lining of blood vessels in the xenograft. The factor(s) which initiates acute vascular rejection is uncertain; however, there is some evidence implicating xenoreactive antibodies. The nature of the humoral response which might contribute to acute vascular rejection of a porcine organ was investigated in baboons which received a porcine cardiac xenograft plus immunosuppression with methylprednisolone, azathioprine, and cyclosporine. Following rejection and surgical removal of the xenografts, the serum concentration of xenoreactive antibodies increased in untreated animals but in immunosuppressed animals was similar to the concentration in preimmune serum. The antibodies in the sensitized recipients were specific for Galalpha1-3Gal (70-95%) and other determinants (5-30%). However, cross-blocking studies showed that, following xenotransplantation, the immunosuppressed baboons had no detectable IgM or IgG directed against "new" endothelial antigens. These results indicate that antibodies made by immunosuppressed individuals in response to xenotransplantation are much like xenoreactive natural antibodies and suggest that acute vascular rejection might in some cases be addressed by therapeutic strategies aimed at those antibodies.

Animals↗
PubMed1997

The role of natural anti-Gal alpha 1-3Gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants.

Xenoreactive natural antibodies in humans and higher primates are directed predominantly at Gal alpha 1-3Gal. These antibodies are thought to initiate hyperacute rejection of porcine organ xenografts. The contribution of anti-Gal alpha 1-3Gal antibodies to the xenoractive natural antibody repertoire and to the initiation of hyperacute rejection was tested in a pig-to-baboon cardiac xenograft model. Anti-Gal alpha 1-3Gal antibodies were depleted from baboons by extracorporeal absorption of anti-Gal alpha 1-3Gal antibodies from plasma using columns with a matrix bearing Gal alpha 1-3Galb1-4GlcNAc. Specific removal of anti-Gal alpha 1-3Gal antibodies was achieved prior to transplantation as demonstrated by immunoassay. Porcine hearts were then transplanted into these baboons and the outcome of the transplants was analysed. Immunofluorescence revealed little deposition of baboon antibodies in the grafts. The porcine hearts did not undergo hyperacute rejection even though complement activity was approximately 90% of baseline at the time of transplantation. These findings demonstrate that anti-Gal alpha 1-3Gal antibodies constitute a major fraction of xenoreactive natural antibodies in primate blood and that these antibodies contribute significantly to the pathogenesis of hyperacute xenograft rejection.

Acute Disease↗
PubMed1997

Specificity and function of "natural" antibodies in immunodeficient subjects: clues to B cell lineage and development.

The origin of natural antibodies has long been a subject of controversy. Polyreactive natural antibodies recognize multiple ligands and are thought to arise from B1 B cells. Natural antibodies against carbohydrate antigens such as Gal alpha 1-3Gal or against blood groups A and B are thought to be "elicited" by gut bacteria, but their origin is uncertain. To explore the origin of naturally occurring anticarbohydrate antibodies, the specificity and function of the xenoreactive antibodies and isohemagglutinins were investigated in immunodeficient subjects. Subjects with defects in T cell-dependent antibody synthesis had normal levels of xenoreactive natural antibodies, most of which, like xenoreactive antibodies from normal individuals, were specific for Gal alpha 1-3Gal. On the other hand, some subjects with hyper-IgM syndrome who were able to synthesize abundant quantities of xenoreactive antibodies and polyreactive antibodies were devoid of anti-Gal alpha 1-3Gal antibodies. These results suggest that the lineages of B cells giving rise to anti-Gal alpha 1-3Gal antibodies and isohemagglutinins are distinct from B1 B cells or at least exist at a more "advanced" stage of development than those B1 B cells that give rise to polyreactive antibodies. The findings also suggest that B cells which synthesize anti-Gal alpha 1-3Gal antibodies and isohemagglutinins may be distinct from B2 B cells or exist at a more "primitive" stage of development than B2 B cells that synthesize elicited antibodies in normal individuals.

Adolescent↗
PubMed1997

Approaching the clinical application of xenotransplantation.

Interspecies transplantation or xenotransplantation is seen increasingly as a potential approach to overcoming the severe shortage of human organs and tissues for transplantation. Much has been learned recently about the immunologic hurdles of transplanting porcine organs into humans. These hurdles can be addressed, in part, by the genetic engineering of donors and by specific therapies directed at the salient immune events. As we succeed in dealing with the immunologic aspects of xenotransplantation, other issues, including zoonosis, and regulatory aspects will need to be addressed.

Animals↗
PubMed1997

The prospects for xenotransplantation of the kidney.

A severe shortage of transplant donors has led to a markedly prolonged waiting time for renal transplantation and has thus sparked interest in the use of animals in lieu of humans as a source of kidneys for transplantation. Clinical application of xenotransplantation is limited in large part by the severe immunologic reaction of the recipient against the graft. This immunologic reaction is mediated initially by components of natural immunity, such as xenoreactive antibodies, complement and natural killer cells, and later by elicited humoral and cellular immune responses that act in concert to disrupt the function of the endothelial lining of blood vessels. The past few years have brought considerable progress in elucidating the molecular and cellular basis of xenograft rejection and in developing strategies to overcome it.

Animals↗
PubMed1997

Tumor infiltrating lymphocytes in squamous cell carcinoma of the head and neck: mechanisms of enhancement using prostaglandin synthetase inhibitors.

Indomethacin has been shown clinically to inhibit growth of SCCHN (Panje, 1981). This inhibition appears to be due to augmentation of cellular immunity. The inhibitory effect of indomethacin may act by limiting tumor associated prostaglandin E2 production, thereby allowing return of costimulatory cytokines by antigen presenting cells. This would have the net result of relief from host unresponsiveness and promotion of B-cell and CTL differentiation, allowing the individual to mount an effective response. The enhancement of tumor infiltrating lymphocytes in SCCHN seen with indomethacin administration could presumably be further augmented when given in combination with cytokine therapy. Future investigation may allow the biochemical staging of an individuals' tumor to determine the optimal combination of cytokine therapy and prostaglandin inhibition through selective use of NSAID's. The effect of NSAID manipulation of prostaglandin and leukotriene metabolism on prevention of metastatic disease in SCCHN has yet to be studied. Given that a preselected, potentially responsive subset of immunocytes exists within the tumor tissue and lymph nodes, the development of the LAK phenomenon in TIL's and tumor draining lymph nodes from surgical specimens is a viable and exceedingly interesting area for future investigations in autologous LAK immunotherapy. The potential exists to harvest a preselected population of tumor infiltrating (Boscia, 1988) or tumor draining immunocytes (McKinnon, 1990). These can then potentially be returned to a state of antigen responsiveness with a combination of cytokine exposure (e.g. rIL-2) and systemic cytokine therapy. With subsequent inhibition of tumor associated prostaglandin synthesis by the systemic administration of prostaglandin synthesis inhibitors, it may be possible to successfully alter the host response to tumor.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Modulation of natural IgM binding and complement activation by natural IgG antibodies: a role for IgG anti-Gal alpha1-3Gal antibodies.

The most abundant natural IgG Abs in human serum are thought to be Abs specific for Gal alpha1-3Gal, a carbohydrate expressed in lower mammals. IgG Abs specific for Gal alpha1-3Gal have been postulated to contribute to host defense and to participate in the rejection of interspecies organ grafts. Our previous studies indicated, however, that IgM and not IgG anti-Gal alpha1-3Gal Abs activate complement on foreign surfaces, and thus the physiologic role of IgG anti-Gal alpha1-3Gal remains uncertain. We tested whether the IgG anti-Gal alpha1-3Gal in a human serum might in fact compete with IgM for binding and thus modulate complement fixation by IgM. Several lines of evidence suggested such competition might occur. First, the functional avidity of IgG and IgM for Gal alpha1-3Gal on cell surfaces were nearly within the same order of magnitude, and in some sera the molar concentrations of IgG and IgM anti-Gal alpha1-3Gal were comparable. Second, binding of human IgM to Gal alpha1-3Gal on cell surfaces was inversely correlated with the concentration of IgG anti-Gal alpha1-3Gal in serum. Third, combination of IgG and IgM Abs specific for Gal alpha1-3Gal demonstrated direct competition for binding. The presence of IgG anti-Gal alpha1-3Gal, which was predominantly IgG2, attenuated by up to 80% the fixation of C1q mediated by IgM, presumably by competing for antigenic sites recognized by IgM Abs that fix complement. Thus, IgG Abs specific for Gal alpha1-3Gal modulate complement activation by IgM specific for that structure and might in this way modulate the consequences that ensue when human blood is brought into contact with foreign organisms or xenogenic cells.

Animals↗
PubMed1996

Differential expression of natural killer cell markers: human versus baboon.

The use of baboons as a model for the study of allo- and xenotransplantation has become increasingly important, but there are few studies on the basic immunological responses in baboons that might be relevant for a rejection reaction. In present study, the cell-surface phenotype, cytokine-induced activation and growth, and cytotoxicity of baboon and human natural killer (NK) and lymphokine-activated killer (LAK) cells were compared. A panel of murine monoclonal antibodies specific for human cell-surface markers expressed on lymphocytes was used to compare relevant baboon and human peripheral blood lymphocytes (PBL). Baboon PBL were 52.1+/-2.9% CD8+, 18.5+/-2.2% CD16+, 3.0+/-0.5% CD25+, and 5.5+/-1.8% CD69+. The corresponding proportions in humans were 23.8+/-7.1%, 12.8+/-3.2%, 4.5+/-1.0%, and 2.3+/-1.1%. In contrast to human PBL, less than 1% of baboon lymphocytes expressed CD56, CD57, and CD122 (interleukin [IL]-2Rbeta). Baboon lymphocytes showed NK cytotoxic activity against the human K562 and CEM cell lines, which was comparable to human NK activity. Depletion of baboon CD16+ or CD8+ cells led to dramatic decreases in NK cytotoxicity, and removal of both subsets completely abrogated NK activity. Incubation of baboon lymphocytes with human recombinant IL-2 for 1 week led to the appearance of CD56+ cells (11.3+/-2.8%). Most of the baboon CD56+ cells induced in culture were in S and G2 phases of cell cycle. Both baboon and human IL-2-activated lymphocytes were highly cytotoxic against the human LAK-sensitive cell line Daudi. Depletion of baboon CD8+ but not CD56+ cells significantly decreased LAK activity. These studies revealed differences in the NK system of humans and baboons that should be taken into consideration when analyzing immune responses to allo- and xenotransplantation in baboons.

Animals↗