Syme oration. Leadership in surgery.
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Biomedical subjects
Peter J Morris
Publications and source records attributed to Peter J Morris.
Mouse endothelial CD40 expression does not play a role during the development of transplant arteriosclerosis.
Endothelial cells (ECs) are of major interest in allograft rejection. The authors and others have recently shown in different mouse allograft models that, during the development of transplant arteriosclerosis, donor ECs are replaced by recipient ECs. It was the aim of this study to characterize the phenotype of ECs during the development of transplant arteriosclerosis further, with particular interest in their capability to express CD40. Abdominal aortic allografts were transplanted across a full major histocompatibility complex (MHC) barrier using BALB/c (H-2d) mice as donors and C57BL/6 (H-2b) mice as transplant recipients. Aortic allografts were harvested on days 7 and 30 after transplantation and analyzed by double-immunohistochemistry for expression of CD40 and CD31. As the authors have previously shown that ECs in the aortic allograft model are of donor origin on day 7 after transplantation, whereas by day 30 donor ECs have been replaced by ECs of recipient origin, these two time points were chosen for analysis of CD40 expression. Double-immunohistochemistry for CD40 and CD31 revealed no endothelial expression of CD40 at either time point. These initial results obtained with the anti-CD40 monoclonal antibody (mAb) (clone 3/23) were confirmed by two further experiments using two different anti-CD40 mAbs (clone HM40-3 and clone 1/10) that bind to epitopes of the CD40 receptor distinct to that of 3/23. Neither mAb revealed endothelial expression of CD40. Further analysis of the composition of the cellular infiltrate demonstrated that the majority of macrophages were CD40 positive. The data indicate that in this mouse model of aortic transplantation, neither recipient- nor donor-derived ECs express CD40 during the development of transplant arteriosclerosis. Therefore, in contrast to rat or human ECs, CD40 expression by mouse ECs does not seem to play a major role in this form of allograft rejection.
Animals↗
Platelet-endothelial cell adhesion molecule-1 (CD31) expression on donor endothelial cells attenuates the development of transplant arteriosclerosis.
BACKGROUND: Platelet-endothelial cell adhesion molecule(PECAM)-1 (CD31) is expressed on the surface of endothelial cells, platelets, monocytes, neutrophils, and certain T-cell subsets. Treatment of endothelial cells with anti-PECAM-1 antibody inhibits leukocyte transmigration. This study was designed to test the hypothesis that, in transplantation, the absence of PECAM-1 expression on donor endothelial cells would reduce the number of leukocytes transmigrating into the allograft, thereby attenuating the development of transplant arteriosclerosis. METHODS: PECAM-1 and PECAM (C57BL/6/H2 ) abdominal aortic allografts were transplanted into BALB/c (H2 ) recipients; syngeneic grafts were used as controls. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of intragraft cytokine mRNA production. RESULTS: Intimal proliferation was exacerbated in PECAM-1 grafts (57+/-5% for PECAM-1 vs. 36+/-6% for PECAM-1; <0.005; n=6). The absence of PECAM-1 expression on donor endothelial cells did not reduce the overall number of graft-infiltrating cells significantly but instead resulted in a significant increase in infiltration by macrophages (F4/80 cells), leading to significantly elevated intragraft mRNA expression of inducible nitric oxide synthase. During the development of transplant arteriosclerosis, PECAM-1 donor endothelial cells were replaced by recipient PECAM-1 endothelial cells, a process that occurred only in the allogeneic situation. Endothelial replacement commenced 14 days after transplantation and was complete by day 30. CONCLUSIONS: These data suggest that PECAM-1 expression by donor endothelial cells attenuates the development of transplant arteriosclerosis, possibly by affecting macrophage infiltration.
Animals↗
The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1).
We have previously shown that the anti-apoptotic transcription factor, Brn-3a and the pro-apoptotic p53 factor have antagonistic effects on the promoter of the gene encoding the anti-apoptotic Bcl-2 protein, with p53 abolishing activation by Brn-3a. Here we demonstrate that this antagonism is also observed on the gene encoding the pro-apoptotic Bax protein with Brn-3a abolishing the ability of p53 to activate the Bax promoter and induce Bax protein expression. In contrast, Brn-3a and p53 co-operative to induce maximal activation of another p53 target gene encoding the cyclin dependent kinase inhibitor, p21(CIP1/Waf1). These differential effects of Brn-3a on p53-inducible genes involved in apoptosis or growth arrest are paralleled by its effects on these processes themselves. Thus, we show that Brn-3a antagonises the anti-apoptotic effect of p53 but co-operates with p53 to induce cell cycle arrest. The potential role of Brn-3a in determining the outcome of enhanced p53 levels is discussed.
Apoptosis↗
Linked unresponsiveness: early cytokine gene expression profiles in cardiac allografts following pretreatment of recipients with bone marrow cells expressing donor MHC alloantigen.
Linked unresponsiveness operates to induce specific unresponsiveness to fully mismatched vascularized allografts in recipients pretreated with anti-CD4 antibody and syngeneic bone marrow cells expressing a single donor MHC class I alloantigen. The aim of the study was to evaluate early post transplant cytokine expression in allografts where linked unresponsiveness was required for long term graft survival. CBA (H2(k)) mice were pretreated with CBK (H2(k)+K(b)) bone marrow cells under the cover of anti-CD4 antibody 28 days before transplantation of a CBK or a C57BL/10 (H2(b)) cardiac allograft. In both cases graft survival was prolonged (MST=100 days). Intragraft expression for interferon (IFN)-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12(p40), IL-18, iNOS, transforming growth factor (TGF)-beta(1) and C-beta was determined on day 1.5, 3, 7 and 14 after transplantation. Whereas rejecting allografts displayed a sharp peak in IFN-gamma, IL-2, IL-4 and IL-10 expression, non-rejecting allografts were characterized by an initial TGF-beta(1) and IFN-gamma production. An increasing IL-4 expression towards day 14 was a unique feature of linked unresponsiveness. All non-rejecting allografts were characterized by an increasing IL-12(p40) production towards day 14. In summary, the early cytokine expression pattern in allografts after bone marrow induced operational tolerance is influenced by the quantity of donor alloantigens expressed on the graft as well as on the bone marrow inoculum.
Animals↗
Kinetics of transplant arteriosclerosis in MHC-Class I mismatched and fully allogeneic mouse aortic allografts.
INTRODUCTION: Transplant arteriosclerosis is still the major complication for long-term allograft survival in clinical transplantation. The aim of our study was to investigate the impact of MHC disparity on the kinetics of the development of transplant arteriosclerosis. METHODS: MHC-class I mismatched CBK (H2k+Kb) or fully allogeneic C57BL/10 (H2b) aortic allografts were transplanted into CBA.CA (H2k) recipients; syngeneic grafts were used as controls. Aortic grafts were analyzed on days 7, 14, and 30 after transplantation by performing morphometry, immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of intragraft cytokine mRNA production. Donor specific alloantibody production was measured by FACS analysis. RESULTS: Intimal proliferation developed more rapidly in fully allogeneic grafts (direct and indirect allorecognition by CD4+ T cells) compared to MHC-class I mismatched grafts (indirect allorecognition only by CD4+ T cells) (day 7: 6+/-7 vs. 2+/-3%; day 14: 17+/-8 vs. 5+/-1%; day 30: 65+/-5 vs. 38+/-7% (C57BL/10 vs. CBK). However, by day 60, the level of intimal proliferation in the MHC-class I mismatched grafts was equivalent to that observed with fully allogeneic grafts on day 30. There was also a marked delay in the kinetics of graft infiltration by CD4+, CD8+, CD11b+, and CD40+ leukocytes and alloantibody production when CD4+ T cells were only activated via indirect presentation (MHC-class I mismatched grafts). Expression of interferon-gamma, interleukin-2, and interleukin-4 correlated with the kinetics of leukocyte infiltration, whereas interleukin-10, interleukin-12p40, iNOS, and TGF-beta1 showed a distinct pattern of expression. CONCLUSIONS: These data demonstrate that the degree of MHC incompatibility between donor and recipient markedly influences the kinetics of the development of transplant arteriosclerosis. The onset of disease was delayed when grafts were mismatched for only MHC-class I antigens, but ultimately reached the same levels as seen in fully allogeneic grafts. The pattern of leukocyte infiltration and the kinetics of cytokine production suggest that in the MHC-class I mismatched grafts CD4+ T cells responding via the indirect pathway might play an important role in the development of transplant arteriosclerosis.
Animals↗
Indirect allorecognition can play an important role in the development of transplant arteriosclerosis.
BACKGROUND: Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. METHODS: Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG (-/-) mice. Immunodeficient mice were reconstituted with either CD4(+) (indirect) or CD8(+) (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. RESULTS: Reconstitution of athymic nude mice with 4 x 10(7) purified CD4(+) T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24+/-8% and did not decrease when nude-derived endogenous CD8(+) T cells were depleted from the nude recipients (intimal proliferation, 21+/-7%). Transplant arteriosclerosis initiated by CD4+ T cells was associated with the presence of intragraft mRNA for interferon-gamma, tumor necrosis factor-alpha, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1(-/-) mice with 4 x 10(7) purified CD4(+) T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20+/-9%) in MHC class I mismatched aortic grafts in the absence of alloantibody production. CONCLUSION: Indirect recognition of donor MHC class I molecules by CD4(+) T cells can play an important role in the process of transplant arteriosclerosis. CD8(+) T-cell effector function and alloantibody production in this model are dependent on CD4(+) T-cell help after indirect allorecognition.
Adoptive Transfer↗
The outcome of pediatric cadaveric renal transplantation in the UK and Eire.
An analysis of all pediatric cadaveric renal transplant recipients in the UK and Eire was undertaken to review the outcomes of pediatric cadaveric renal transplantation and to consider the implications for organ allocation procedures for pediatric recipients. Factors influencing the outcome of 1,252 pediatric cadaveric renal transplants in the UK and Eire in the 10-yr period from 1 January 1986 to 31 December 1995 were analyzed by Cox proportional hazards regression, including analysis of four distinct post-transplant epochs (0-3 months, 3-12 months, 12-36 months, and beyond 36 months). At the time of analysis (December 2000), 113 (11%) recipients had died and 47% of grafts had failed. In the multi-factorial modelling, the factors significantly affecting transplant outcome were cold ischaemia time, donor and recipient age and human leucocyte antigen (HLA) matching. Epoch analysis demonstrated that these factors operated at different times post-transplant. Cold ischaemia time had a strong influence on outcome at 3 months. A highly significant increased risk of graft failure was associated with donors under 5 yr of age. Young recipients had an increased risk of failure in the short term, but beyond 1 yr post-transplant there were few failures in young recipients while a steady rate of graft loss persisted in the older children. In terms of HLA matching, the worst outcome was observed for two HLA-DR mismatched grafts, while 000 and favorably matched kidneys (100, 010, 110 HLA-A, -B, -DR mismatches) survived longest. Hence, a policy of exchanging organs on the basis of HLA matching is justified for 000 mismatched and favorably matched kidneys. The poor outcome associated with very young donors should discourage pediatric units from transplanting kidneys from such young donors. The reasons for late losses in older recipients need investigation.
Cause of Death↗
Lecithinized superoxide dismutase reduces cold ischemia-induced chronic allograft dysfunction.
BACKGROUND: Chronic renal allograft failure (CAF) is influenced by both allo-dependent and independent factors and is a major cause of graft loss in clinical renal transplantation. We evaluated a novel membrane-bound free radical scavenger, lecithinized superoxide dismutase (lec-SOD), to determine its potential in limiting the harmful effects of ischemia/reperfusion injury on CAF. METHODS: Fisher rat kidneys were stored for either 1 hour or 18 hours in cold Marshall's preservation solution either with or without lec-SOD and transplanted into Lewis recipients. RESULTS: Within 3 days of transplantation, an early inflammatory response involving granulocytes and macrophages was detected in renal allografts exposed to 18 hours cold ischemia that was significantly reduced by preservation with lec-SOD. By 24 weeks post-transplantation, elevated proteinuria and detection of apoptotic cells was observed in kidneys exposed to 18 hours of cold ischemia, that was attenuated by preservation with lec-SOD (P < 0.05). However, up-regulated expression of intracellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) Class II together with a T lymphocyte infiltration were observed at 24 weeks that was not prevented by preservation with lec-SOD. CONCLUSIONS: These results demonstrate that ischemia/reperfusion injury, apoptotic cell death and allo-immune responses may be exacerbated by cold ischemia and accelerate the development of CAF. Preservation with lec-SOD may protect against the early damage induced by cold ischemia and reperfusion injury.
Animals↗