Search PubMed⌕ Search

Biomedical subjects

R Cortesini

Publications and source records attributed to R Cortesini.

At least 55 records · Page 3Linked to original sources
PubMed1998

Intramolecular and intermolecular spreading during the course of organ allograft rejection.

There are two distinct pathways by which T cells may recognize MHC alloantigens. The direct pathway involves T-cell recognition of intact MHC molecules expressed by donor antigen-presenting cells (APCs). The second, or indirect, pathway describes T-cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self APCs. Recent data demonstrates that indirect recognition plays a central role in both acute and chronic rejection of human organ allografts. Our studies have shown that, at the onset of primary acute rejection, recipient T-cell responses to donor HLA-DR alloantigens are limited to a single dominant determinant present on one of the disparate alloantigens and restricted by one of the responder's HLA-DR molecules. In allograft recipients with recurring episodes of rejection, and/or at the onset of chronic rejection, recipient T-cell reactivity may spread to other epitopes within the allogeneic MHC molecule as well as to other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T-cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection. These studies provide a basis for the design of new therapeutic strategies and for immunologic monitoring of transplant recipients.

Graft Rejection↗
PubMed1998

Kidney transplantation from living unrelated donors.

Our center activated our living-related donor (LRD) kidney transplantation program in 1967 and the living-unrelated donor (LURD) kidney transplantation program in 1968. We performed 62 kidney transplants (of which 6 were LURD) under conventional immunosuppression therapy of the period. During the cyclosporine era, our group performed the first living-donor kidney transplant in 1982 and the first LURD transplant in Europe in 1983. Since then 184 LURD transplants (1/3 of all living kidney transplants) took place in our center under cyclosporine therapy. LURD remains a controversial procedure as a consequence of problems related both to the donor's risk, which can be reduced by careful medical evaluation and selection, and to the recipient's outcome, including the importance of HLA compatibility, as well as concerns about the danger of commercialism. According to international evidence, as well as our own experience, LURD kidney transplantation is a safe and effective approach to increase the donor pool. Living donor mortality is extremely low, while long-term graft survival is the same as that observed after LRD transplantation and is superior to that for cadaver donor transplantation. We do not recommend DST because the long-term survival benefits do not justify the risks of sensitization and infections. At least for primary transplants, there is not an increased risk of transplantation from a husband to his wife with previous pregnancies. The pretransplant screening of taboo HLA mismatches could be useful to increase long-term graft survival. It is our opinion that LURD transplantation should be considered at least as good a clinical option as cadaver donor transplantation for patients with end-stage renal failure. A selective advantage of this procedure is that dialysis could be avoided before transplantation, with significant socio-economic benefits and improved recipient quality of life.

Adult↗
PubMed1998

Kidneys derived from mice transgenic for human complement blockers are protected in an in vivo model of hyperacute rejection.

PURPOSE: The major obstacle to successful discordant kidney xenotransplantation is hyperacute rejection (HAR). Complement plays a key role in the induction of HRA, defined by endothelial cell activation, loss of vascular integrity, hemorrhage and thrombosis. The activation of complement is tightly controlled by a number of species-specific regulatory proteins which inhibit, at different points, the cascade of events leading to the formation of the membrane attack complex (MAC). We have tested the hypothesis that kidneys derived from transgenic mice expressing two human complement inhibitors, Decay Accelerating Factor (hDAF) and Membrane Cofactor Protein (MCP), could be protected from human complement-mediated damage. MATERIALS AND METHODS: Control and transgenic mice were perfused with human plasma by cannulation of the right jugular vein, at a perfusion rate of 10 microL./min. for two hours. Complement C3 deposition was detected on kidney sections by immunohistochemistry using specific FITC antibody. Complement-induced tissue damage was evaluated by histopathological examination. RESULTS: Heavy deposition of complement C3 was observed on kidneys derived from perfused control mice. This was associated with a characteristic HAR pathology of severe interstitial hemorrhage, inflammatory reaction, loss of glomerula and tubuli structure. Kidneys derived from mice transgenic for hDAF or hMCP were partially protected from both complement C3 deposition and tissue damage. The expression of both hDAF and hMCP in double transgenic mice significantly increases the protection from human complement-mediated damage. CONCLUSION: A novel model of in vivo perfusion with human plasma has been adopted to recreate the initial event of HAR. Our data show that this murine model could be very valuable to determine the effect of transgenic human molecules in protecting vascularized organs from human complement attack.

Acute Disease↗
PubMed1997

New strategies for early diagnosis of heart allograft rejection.

BACKGROUND: Allograft rejection is mediated by T cells that recognize allogeneic major histocompatibility complex (MHC) molecules via the direct and indirect pathway. The direct pathway involves T cells that react against MHC/peptide complexes expressed on the surface of donor antigen-presenting cells (APCs). In contrast, T cells involved in the indirect pathway recognize peptides derived from processing and presentation of allogeneic MHC molecules by self (recipient) APCs. To explore the relative contribution of these two pathways to rejection, we have evaluated the response of peripheral blood T cells from 50 heart transplant recipients against donor APCs (direct recognition) and against self APCs pulsed with synthetic peptides corresponding to the hypervariable region of the mismatched HLA-DR antigens of the donor (indirect recognition). METHODS: T cell reactivity against donor APCs was quantitated by measuring the expression of CD69 on allostimulated CD3+ LDA1+ cells. Reactivity to synthetic allopeptides was determined in limited dilution assays. RESULTS: Serial studies of the kinetics of direct and indirect recognition showed that both pathways contribute to early acute rejection episodes. Primary rejection was accompanied invariably by indirect recognition of a dominant allopeptide. Intermolecular spreading of T cell epitopes was observed during recurrent rejections. Enhanced recognition of donor alloantigens via the direct pathway was found predominantly during early rejection episodes. A single form of allorecognition was shown to occur in some rejection episodes. CONCLUSIONS: Monitoring of the direct and indirect pathway of allorecognition provides a reliable method for prediction and differential diagnosis of acute rejection of heart allografts.

Antigen-Presenting Cells↗
PubMed1997

Allopeptide-specific T cell reactivity altered by peptide analogs.

Recent evidence indicates that indirect allorecognition plays a key role in initiating and sustaining graft rejection. This self-restricted T cell response is generally limited to a restricted set of dominant immunogenic peptides derived from allogeneic HLA molecules. Here, we have examined whether peptide analogues of the dominant determinant of HLA-DRbeta1*0101 molecule (peptide DR1/22-35), recognized in the context of HLA-DRbeta1*1101 protein, are able to modulate the T cell response against the wild-type peptide Ag. The peptide analogues were generated by introducing single amino acid substitutions at putative MHC and TCR contact positions. Two analogues, 25R/A and 28E/Q, which bound to soluble DR11 protein, but did not stimulate an anti-DR1-specific T cell clone, inhibited the response of the clone to the wild-type peptide by TCR antagonism. Analogs 25R/A and 28E/Q were also able to inhibit the differentiation of Th precursors specific for peptide DR1/22-35. Two other peptides, 26L/I and 27L/V, acted as powerful TCR agonists, inducing a higher proliferative response of the DR1-specific T cell clone, compared with the wild-type peptide. At high concentrations, these peptides induced hyporesponsiveness of TCC-ZL36 in a manner similar to the wild-type peptide. Taken together, the results of this study indicate that specific suppression of indirect allorecognition can be achieved by using structural variants of the dominant allodeterminant.

Amino Acids↗
PubMed1997

Mechanism of liver allograft rejection: the indirect recognition pathway.

Transplant rejection is mediated by the direct and indirect pathways. To explore the role of the indirect recognition pathway in the rejection of liver allografts, T cells obtained from peripheral blood were expanded in medium containing IL-2 and tested in LDA for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial investigations of 17 recipients showed that T-cell reactivity to donor HLA-DR peptides was strongly associated with acute rejection episodes. In recipients carrying a graft that was mismatched by two HLA-DR alleles, a single donor antigen was targeted during primary rejection, although allopeptide reactivity against the second HLA-DR antigen was observed during subsequent episodes of acute rejection. The finding that allopeptide reactivity occurs early following transplantation and is predictive of rejection is consistent with the notion that processing of donor alloantigens by recipient APCs activates the indirect T-cell recognition pathway that plays a major role in initiating and amplifying allograft rejection.

Antigen Presentation↗
PubMed1996

Indirect recognition of donor HLA-DR peptides in organ allograft rejection.

To determine whether indirect allorecognition is involved in heart allograft rejection T cells obtained from peripheral blood and graft biopsy tissues were expanded in the presence of IL-2 and tested in limiting dilution analysis (LDA) for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial studies of 32 patients showed that T cell reactivity to donor allopeptides was strongly associated with episodes of acute rejection. The frequency of allopeptide reactive T cells was 10-50-fold higher in the graft than in the periphery indicating that T cells activated via the indirect allorecognition pathway participate actively in acute allograft rejection. In recipients carrying a graft differing by two HLA-DR alleles the response appeared to target only one of the mismatched antigens of the donor. Indirect allorecognition was restricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermolecular spreading was demonstrated in patients with multiple rejection episodes by showing that they develop allopeptide reactivity against the second HLA-DR antigen. These data imply that early treatment to suppress T cell responses through the indirect pathway of allorecognition, such as tolerance induction to the dominant donor determinant, may be required to prevent amplification and perpetuation of the rejection process.

Cells, Cultured↗
PubMed1996

The role of preoperative investigations in predicting difficult laparoscopic cholecystectomies. Results in 200 consecutive cases.

BACKGROUND: When we began laparoscopic cholecystectomy (LC) we set up a strict preoperative workup in order to assess whether currently available investigations could help predict difficult laparoscopic procedures. METHODS: Reported here are the results of a prospective trial carried out in our first 200 consecutive patients, who underwent routine intravenous cholangiography (IVC), abdominal ultrasound scan (US), blood tests-namely, markers of biliary stasis (MBS)-and preoperative endoscopic retrograde cholangiopancreatography (ERCP) in case of clinically suspected common bile duct stones (CBDS). RESULTS: On the basis of our experience we think that the US findings relate to the difficulty of the laparoscopic procedure more closely than the other preoperative investigations, and the association of US and liver chemistry provides an accurate evaluation of biliary stones. CONCLUSIONS: In agreement with data emerging from the literature, the preoperative investigations do not seem to be useful in predicting biliary and vascular complications, whose prevention lies in the adoption of correct surgical technique and a low threshold for conversion.

Adult↗
PubMed1996

Hemodynamic and metabolic effects of transjugular intrahepatic portosystemic shunt (TIPS) during anesthesia for orthotopic liver transplantation.

Recently, the transjugular intrahepatic portosystemic shunt (TIPS) has been advocated as a safe bridge to orthotopic liver transplantation (OLT). We retrospectively studied 53 consecutive cirrhotic patients who underwent OLT: 27 patients with TIPS were compared to 26 controls. Hemodynamic and oxyphoretic data (Fick method) were collected during six phases of OLT. There were no significant differences in demographic data and Child-Pugh class, nor in surgical time and blood product requirements before the anhepatic phase between TIPS patients and controls. In the TIPS group, we observed a marked hyperdynamic profile with a lower systemic vascular resistance index, higher cardiac index, and depressed oxygen consumption before native liver removal. During the same period, the TIPS group developed a greater acidosis and was treated with a larger amount of NaHCO3. Following the anhepatic phase, no differences between the two groups were detected. All transplantations were successful, and no complications related to TIPS were observed. These results seem to be the consequence of a reduced liver function reserve with a direct hemodynamic effect due to the TIPS.

Acidosis↗
PubMed1996

New approaches to specific immunomodulation in transplantation.

T cells can recognize foreign MHC antigens by two distinct routes, either directly as intact molecules, or indirectly as processed peptides. Recent evidence strongly suggests that the indirect pathway of allorecognition plays a key role in initiating and sustaining graft rejection. Theoretically, all mismatched HLA alloantigens could generate immunogenic peptides which may be recognized in the context of any of the two self HLA-DR molecules. However, indirect recognition appears to be limited to a single peptide determinant of an allogeneic HLA-DR molecule and restricted by one self HLA-DR molecule. Furthermore, T cells involved in the self-restricted allopeptide recognition express a limited array of T cell receptor variable genes. These findings suggest that selective immune interventions, such as peptide blockade of the self HLA-DR molecule involved in the presentation of the dominant allopeptide, induction of high-zone tolerance or TCR antagonism, may be devised to prevent graft rejection.

Antigen Presentation↗