%0 Journal Article
%~ PubMed
%A Zhao, Xiangdong
%A Li, Ying
%A Ohe, Hidenori
%A Nafady-Hego, Hanaa
%A Uemoto, Shinji
%A Bishop, G Alex
%A Koshiba, Takaaki
%T Intragraft Vδ1 γδ T Cells With a Unique T-Cell Receptor Are Closely Associated With Pediatric Semiallogeneic Liver Transplant Tolerance.
%B Transplantation
%D 2013
%C United States
%I Lippincott Williams & Wilkins
%V 95
%N 1
%P 192-202
%@ 0041-1337
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Ganbold, Anar
%A Andersen, Sean
%A Tay, Szun S
%A Cunningham, Eithne
%A Ilie, Victor
%A Krishnan, Sai
%A Wang, C
%A McCaughan, Geoffrey W
%A Sharland, Alexandra F
%A Bishop, G Alex
%T Expression of common gamma chain signalling cytokines and their receptors distinguishes rejection from tolerance in a rat organ transplant model.
%B Transplant Immunology
%D 2012
%C Netherlands
%I Elsevier BV
%V 27
%N 2-3
%P 89-94
%@ 1878-5492
%X BACKGROUND: Signalling through the cytokine common ?? chain (??c) is crucial for survival of activated T cells. In its absence, severe combined immunodeficiency ensues and transplanted tissues are not rejected. METHODS: To determine whether differences in the availability of ??c signalling cytokines correlate with rejection or acceptance, we examined expression of all ??c signalling components in organs transplanted between PVG donors and DA recipients. In this combination hearts or kidneys are rejected in <10days while livers survive >100days. Expression of the ??c cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 and their receptors ??c, IL-2R??, IL-2R??/IL-15R??, IL-4R??, IL-7R??, IL-9R??, IL-15R?? and IL-21R?? was determined by real-time PCR pre-transplant and on days 3, 5 and 7 after transplantation. RESULTS: Most increased after transplantation, although there were significantly lower levels of IL-2, IL-2R??, IL-4 and IL-15R?? in tolerant livers compared to rejecting hearts or kidneys. IL-9 was only expressed in normal kidneys and decreased during rejection. IL-15 was constitutively expressed and did not change after transplantation. IL-21 and IL-21R increased in all transplanted organs to a similar extent. IL-7R?? in liver was considerably increased compared with heart or kidney, consistent with its known inverse relationship to global levels of ??c signalling. CONCLUSIONS: In transplanted livers, acceptance is associated with low levels of all ??c cytokines or receptors except IL-21. This is consistent with "dilution" of ??c cytokines from a finite clone size of alloreactive T cells in livers, which are ten times larger than kidneys or hearts.
%Z FOR Codes: 1104 1109


%0 Journal Article
%~ PubMed
%A Ohe, Hidenori
%A Waki, Kayo
%A Yoshitomi, Mami
%A Morimoto, Takeshi
%A Nafady-Hego, Hanaa
%A Satoda, Naoki
%A Li, Ying
%A Zhao, Xiangdong
%A Sakaguchi, Shimon
%A Uemoto, Shinji
%A Bishop, G Alex
%A Koshiba, Takaaki
%T Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match*
%B Transplant international : official journal of the European Society for Organ Transplantation
%D 2012
%C Germany
%I Wiley-Blackwell Publishing Ltd.
%V 25
%N 1
%P 97-106
%@ 1432-2277
%X Pediatric recipients of living-donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi-allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post-Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr-tol), but not in 50 intolerant patients (Gr-intol). The Gr-intol consisted of 24 patients with rejection (Gr-rej) and 26 with fibrosis of grafts (Gr-fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11-7.02, P = 0.03], was a positive independent predictor, whereas HLA-A mismatch (0.18, 0.03-0.91, P = 0.04) was a negative predictor. HLA-DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr-intol (4.9%) compared with Gr-tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr-Tol (P = 0.02). Although HLA-B mismatch (8.73, 1.09-70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA-A match and the later predominance of Tregs are factors associated with OT.
%Z FOR Codes: 110323 110708


%0 Journal Article
%~ PubMed
%A Cubitt, Jonathan
%A Pennington, Thomas
%A Wang, Chuanmin
%A Allen, Richard
%A Bishop, Alex
%A Sharland, Alexandra
%T Reliable and reproducible murine models for commonly used abdominal plastic surgical flaps.
%B Journal of Reconstructive Microsurgery
%D 2012
%C United States
%I Thieme Medical Publishers
%V 28
%N 3
%P 161-166
%@ 1098-8947
%X Animal models have been used for many years in surgical research to develop different surgical techniques, improve understanding of anatomy and physiology and hone surgical skills. The benefit of such models has been particularly important in developing relatively young specialties like plastic surgery and many plastic surgical techniques are designed and studied in animals long before they are used in humans. We describe techniques for raising several reliable and reproducible abdominal flaps in rodents, including transverse rectus abdominis myocutaneous flaps in rats and mice, superficial inferior epigastric artery flaps in rats and perforator flaps in rats. The intention of this paper is to act as a point of reference for any microvascular or plastic surgeon who is planning to perform abdominal plastic surgical flap research or further microvascular skills.
%Z FOR Codes: 110323


%0 Journal Article
%~ PubMed
%A Alex Bishop, G
%A Bertolino, Patrick D
%A Bowen, David G
%A McCaughan, Geoffrey W
%T Tolerance in liver transplantation.
%B Best Practice & Research. Clinical Gastroenterology
%D 2012
%C United Kingdom
%I Bailliere Tindall
%V 26
%N 1
%P 73-84
%@ 1532-1916
%X Operational tolerance (OT) in liver transplant patients occurs much more frequently than OT of other transplanted organs; however the rate of OT varies considerably with the centre and patient population. Rates of OT range from 15% of the total liver transplant (LTX) patient population down to less than 5%. This review examines the reports of liver OT and compares the factors that could contribute to this variation. Multiple factors were examined, including the time from transplantation when weaning of immunosuppression (IS) was commenced, the rapidity of weaning, the contribution of maintenance and induction IS and the patient population transplanted. The approaches that might be used to increase the likelihood of OT are discussed and the approaches to monitoring OT in LTX patients are reviewed.
%Z FOR Codes: 110307 110708


%0 Journal Article
%~ PubMed
%A Bishop, G Alex
%A Ierino, Francesco L
%A Sharland, Alexandra F
%A Hall, Bruce M
%A Alexander, Stephen I
%A Sandrin, Mauro S
%A Coates, P Toby
%A McCaughan, Geoffrey W
%T Approaching the Promise of Operational Tolerance in Clinical Transplantation.
%B Transplantation
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 91
%N 10
%P 1065-1074
%@ 0041-1337
%X Long-term acceptance of transplanted organs without requirement for indefinite immunosuppression remains the ultimate goal of transplant clinicians and scientists. This clinical state of allograft acceptance termed "operational tolerance" has been elusive in routine practice. However, there are published reports of recipients where immunosuppression has been discontinued, by intention or patient noncompliance, in which the outcome is a nondestructive immune response and normal function. The question now arises how clinical operational tolerance might be achieved in the majority of recipients. This review provides an overview of current approaches to achieve operational tolerance, including the use of donor bone marrow and depletion of recipient T cells and the resistance of liver transplants to rejection. It also describes the key role of clinical immune monitoring and future approaches to tolerance induction including inhibition of T-cell signaling, manipulation of costimulatory pathways, and expansion of regulatory T cells. The principles of these experimental approaches may ultimately be extended to provide safe and effective control of transplant rejection and induction of clinical operational tolerance.
%Z FOR Codes: 111403


%0 Journal Article
%~ PubMed
%A van Leest, Yvette
%A Moroso, Viviana
%A Wang, Chuanmin
%A Tay, Szun Szun
%A Cunningham, Eithne
%A Ilie, Victor
%A Bishop, Alex
%A Kwekkeboom, Jaap
%T No evidence for involvement of donor NK cells in liver transplant tolerance.
%B Transplant immunology
%D 2011
%C Netherlands
%I Elsevier BV
%V 24
%N 2
%P 138-9
%@ 1878-5492
%X 
%Z FOR Codes: 110312


%0 Journal Article
%~ PubMed
%A Bishop, G Alex
%A Sharland, Alexandra F
%A Ierino, Francesco L
%A Sandrin, Mauro S
%A Hall, Bruce M
%A Alexander, Stephen I
%A Coates, P Toby
%A McCaughan, Geoffrey W
%T Operational Tolerance in Organ Transplantation Versus Tissue Engineering: Into the Future.
%B Transplantation
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 92
%N 8
%P e39
%@ 0041-1337
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Wang, Chuanmin
%A Cordoba, Shaun
%A Hu, Min
%A Bertolino, Patrick
%A Bowen, David G
%A Sharland, Alexandra F
%A Allen, Richard D M
%A Alexander, Stephen I
%A McCaughan, Geoffrey W
%A Bishop, G Alex
%T Spontaneous acceptance of mouse kidney allografts is associated with increased Foxp3 expression and differences in the B and T cell compartments.
%B Transplant immunology
%D 2011
%C Netherlands
%I Elsevier BV
%V 24
%N 3
%P 149-56
%@ 1878-5492
%X Spontaneous acceptance of organ allografts can identify novel mechanisms of drug-free transplantation tolerance. Spontaneous acceptance occurs in both mouse kidney transplants and rat liver transplants however the early immune processes of mouse kidney acceptance have not been studied. Acceptance of C57BL/6 strain kidney allografts in fully MHC-incompatible B10.BR recipients was compared with rejection (REJ) of heart allografts in the same strain combination. Graft infiltrate and antibody deposition were examined by immunohistochemical staining. Expression of mRNA was measured by quantitative real-time PCR. Apoptosis was examined by TUNEL staining. The majority of kidney allografts were accepted long-term and induced tolerance (TOL) of donor-strain skin grafts, showing that acceptance was not due to immune ignorance. There was an extensive infiltrate of T cells in the TOL kidney that exceeded the level in REJ hearts but subsequently declined. The main differences were deposition of IgG2a antibody in REJ that was absent in TOL, more B cells infiltrating TOL kidneys and a progressive increase in the ratio of CD8:CD4 cells during rejection. There was also significantly greater Foxp3 mRNA expression in TOL. Kidneys from RAG-/- donors were accepted, showing that donor lymphocytes were not necessary for acceptance. Neutralising antibodies to TGF-?? administered from day 0 to day 6 did not prevent TOL. On the basis of cytokine expression and apoptosis there was no evidence for immune deviation or deletion as mechanisms of acceptance. In accord with the findings of spontaneous acceptance of liver allografts in rats, the main difference between mouse kidney TOL and heart REJ was in the B cell compartment. The major difference to rat liver allograft acceptance was that apoptosis of infiltrate did not appear to play a role. Instead, increased Foxp3 expression in TOL kidneys implies that regulatory T cells might be important.
%Z FOR Codes: 1103 1107


%0 Journal Article
%~ PubMed
%A Wang, Chuanmin
%A Tay, Szun Szun
%A Tran, Giang T
%A Hodgkinson, Suzanne J
%A Allen, Richard D M
%A Hall, Bruce M
%A McCaughan, Geoffrey W
%A Sharland, Alexandra F
%A Bishop, G Alex
%T Donor IL-4 treatment induces alternatively activated liver macrophages and IDO-Expressing NK cells and promotes rat liver allograft acceptance.
%B Transplant immunology
%D 2010
%C Netherlands
%I Elsevier BV
%V 22
%N 3-4
%P 172-8
%@ 1878-5492
%X Most approaches to transplant tolerance involve treatment of the recipient to prevent rejection. This study investigates donor treatment with IL-4 for its effect on subsequent rat liver allograft survival. Rat orthotopic liver transplants were performed in rejecting (PVG donor to Lewis recipient) or spontaneously tolerant (PVG to DA) strain combinations. Donors were untreated or injected intraperitoneally with IL-4 (30,000U/day) for 5days. Tissue infiltrates and gene expression were examined by immunohistochemistry and real-time quantitative PCR. IL-4 induced a marked leukocyte infiltrate in donor livers prior to transplant. Macrophages comprised the major population, although B cells, T cells and natural killer (NK) cells also increased. IL-4-induced liver macrophages had an alternatively activated phenotype with increased expression of mannose receptor but not inducible nitric oxide synthase (NOS2). IL-4 also induced IDO and IFN-gamma expression by NK cells. Donor IL-4-treatment converted rejection to acceptance in the majority of Lewis recipients (median survival time >96days) and did not prevent acceptance in DA recipients. Acceptance in Lewis recipients was associated with increased donor cell migration to recipient spleens and increased splenic IL-2, IFN-gamma and IDO expression 24h after transplantation. Donor IL-4-treatment increased leukocytes in the donor liver including potentially immunosuppressive populations of alternatively activated macrophages and IDO-expressing NK cells. Donor treatment led to long-term acceptance of most livers in association with early immune activation in recipient lymphoid tissues.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Sharland, Alexandra
%A Logan, Grant J
%A Bishop, Alex
%A Alexander, Ian E
%T Liver-directed gene expression using recombinant AAV 2/8 vectors -- a tolerogenic strategy for gene delivery?
%B Discovery Medicine
%D 2010
%C United States
%I Solariz, Inc.
%V 9
%N 49
%P 519-527
%@ 1944-7930
%X Vectors based on recombinant adeno-associated virus (AAV) 2/8 hold considerable promise for use in human gene therapy. These vectors are safe, and have minimal immunostimulatory properties. Their combination with efficient, liver-specific promoters allows high-level transgene expression in the hepatocytes of small and large animals. In small animal models, this high level of liver expression results in tolerance to the transgene products. Tolerance to transgene products may also be achievable using these vectors for human gene therapy, but the HLA diversity (and thus variability in T cell recognition of transgene products) and high frequency of prior natural exposure to AAV in human populations impose additional challenges that must be overcome in order for this strategy to succeed.
%Z FOR Codes: 100401


%0 Journal Article
%~ PubMed
%A Laurence, Jerome M
%A Allen, Richard D M
%A McCaughan, Geoffrey W
%A Logan, Grant J
%A Alexander, Ian E
%A Bishop, G Alex
%A Sharland, Alexandra F
%T Gene therapy in transplantation.
%B Transplantation Reviews
%D 2009
%C United States
%I WB Saunders Co.
%V 23
%N 3
%P 159-170
%@ 1557-9816
%X Gene therapy is an exciting and novel technology that offers the prospect of improving transplant outcomes beyond those achievable with current clinical protocols. This review explores both the candidate genes and ways in which they have been deployed to overcome both immune and non-immune barriers to transplantation success in experimental models. Finally, the major obstacles to implementing gene therapy in the clinic are considered.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Laurence, Jerome M
%A Wang, Chuanmin
%A Zheng, Maolin
%A Cunningham, Sharon
%A Earl, John
%A Tay, Szun Szun
%A Allen, Richard D M
%A McCaughan, Geoffrey W
%A Alexander, Ian E
%A Bishop, G Alex
%A Sharland, Alexandra F
%T Overexpression of indoleamine dioxygenase in rat liver allografts using a high-efficiency adeno-associated virus vector does not prevent acute rejection.
%B Liver Transplantation
%D 2009
%C United States
%I John Wiley & Sons, Inc.
%V 15
%N 2
%P 233-241
%@ 1527-6473
%X The aim of this study was to evaluate the ability of local overexpression of indoleamine dioxygenase (IDO) to abrogate rat liver transplant rejection by the use of an adeno-associated virus vector [recombinant adeno-associated virus 2/8 (rAAV2/8)] to deliver the transgene to the allograft prior to transplantation. A green fluorescent protein (GFP)-expressing vector [recombinant adeno-associated virus 2/8-liver-specific promoter 1-enhanced green fluorescent protein (rAAV2/8-LSP1-eGFP)] was used to examine the kinetics of expression and optimal dosing for transduction of Piebald Virol Glaxo (PVG) rat livers. A vector encoding the rat IDO gene (rAAV2/8-LSP1-rIDO) was constructed and tested by its ability to induce tryptophan catabolism and kynurenine production in vitro and in vivo. PVG donor rats were injected, via the portal vein, with rAAV2/8-LSP1-rIDO 2 weeks before transplantation into PVG strain isograft or Lewis (LEW) strain allograft recipients. With the enhanced GFP vector, 29.5% and 47.4% of hepatocytes were found to express GFP at 3 and 6 weeks after injection, respectively. In untransplanted PVG animals, the rAAV2/8-LSP1-rIDO vector induced, 3 weeks after administration, a 1.8-fold increase (P = 0.0161) in liver IDO activity, which was associated with a fall in serum tryptophan to 0.5 times the baseline level (P < 0.001). PVG recipients of PVG liver isografts pretreated with the IDO-expressing vector had a 45% lower level of serum tryptophan than recipients of isografts pretreated with the GFP-expressing vector (P = 0.03). LEW recipients of PVG liver allografts pretreated with the rat IDO vector had a median survival time of 12 days, whereas recipients of allografts pretreated with rAAV2/8-LSP1-eGFP had a median survival time of 13 days (P = 0.38). Both groups displayed similar histological features of acute cellular rejection. In conclusion, rAAV2/8 vectors produce highly efficient, though delayed, hepatocyte transduction in vivo and provide a useful gene delivery tool for transplantation models. However, gene delivery using IDO was unsuccessful in prolonging rat liver allograft survival.
%Z FOR Codes: 110708 100401


%0 Journal Article
%~ PubMed
%A Tay, Szun Szun
%A Plain, Karren M
%A Bishop, G Alex
%T Role of IL-4 and Th2 responses in allograft rejection and tolerance.
%B Current Opinion in Organ Transplantation
%D 2009
%C United States
%I Lippincott Williams & Wilkins
%V 14
%N 1
%P 16-22
%@ 1531-7013
%X PURPOSE OF REVIEW: Due to the dominance of Th1 cytokines in rejection and the ability of Th2 cytokines, particularly IL-4, to inhibit Th1 responses, it has long been held that Th2 cytokines can improve transplant outcomes. Although there is some support for this, there is mounting evidence that IL-4 and Th2 cytokines can promote graft dysfunction. These disparate effects are reviewed. RECENT FINDINGS: The role of Th2 cytokines in graft dysfunction is not necessarily due to promotion of humoral immunity, but is due to their ability to drive T-cell and non-T-cell responses including alternative activation of macrophages. Alternatively, activated macrophages compete with classically activated macrophages for arginine and they are mutually exclusive, analogous to mutual competition between Th1 and Th2 cells. Recent findings also point to two subsets of regulatory T cells (Tregs), each dependent on either Th1 or Th2 cytokines. In addition to its effects on bone marrow-derived cells, IL-4 affects parenchymal cells by signalling through the type II receptor, which consists of the IL-4R alpha chain (IL-4Ralpha) and the IL-13Ralpha1, which also binds IL-13. SUMMARY: The effects of Th2 cytokines in transplantation depend on their cellular targets, the timing and form of administration and on Th2 cytokine-dependent Tregs.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Zamfirescu, D G
%A Owen, E
%A Lascar, I
%A Molitor, M
%A Zegrea, I
%A Popescu, M
%A Bishop, G A
%A Lauer, C A
%A Simionescu, M
%A Climov, M
%A Lanzetta, M
%T Sentinel skin allograft-a reliable marker for monitoring of composite tissue transplant rejection.
%B Transplantation Proceedings
%D 2009
%C United States
%I Elsevier Inc.
%V 41
%N 2
%P 503-508
%@ 0041-1345
%X Previous studies have demonstrated that composite tissue transplants such as limbs reject more slowly than skin transplants. This has led to the hypothesis that a simultaneous skin graft may act as an effective marker of limb rejection. The aim of this study was to test the predictive value of a sentinel skin graft as a marker of rejection, using a hind limb transplantation model in rats. Lewis rat recipients received hind limb transplants alone from a Brown Norway donor (control; n = 15) or combined with a full-thickness 15 cm(2) sentinel skin graft (n = 45). All animals received drug therapy (tacrolimus, mycophenolate mofetil, and prednisone) for 6 weeks; then, treatment was ceased entirely. Rejection of the skin graft and limb skin was assessed both by visual and histologic grading systems. Detectable visual rejection (grade 1) was observed earlier in the sentinel skin graft than in the limb skin (P < .0005); the clearest visual rejection (grade 2) appeared earlier in the sentinel skin graft (P < .005). The average histologic grade for early rejection of the skin graft was 1.46 and 1.08 for the limb skin (P < .05). These findings confirmed a visual and histologic delay in the rejection of limb skin compared with a distant sentinel skin graft. Skin grafts transplanted simultaneously with hind limbs may be a useful marker of early rejection.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Laurence, Jerome M
%A Wang, Chuanmin
%A Park, Euiyoun T
%A Buchanan, Alexandra
%A Clouston, Andrew
%A Allen, Richard D M
%A Mccaughan, Geoffrey W
%A Bishop, G Alex
%A Sharland, Alexandra F
%T Blocking indoleamine dioxygenase activity early after rat liver transplantation prevents long-term survival but does not cause acute rejection.
%B Transplantation
%D 2008
%C United States
%I Lippincott Williams & Wilkins, Inc.
%V 85
%N 9
%P 1357-1361
%@ 0041-1337
%X In a well-characterized rat model of liver transplantation, Piebald Virol Glaxo strain livers are accepted long term in fully mismatched Dark Agouti recipients (tolerance; TOL), but rejected in Lewis recipients (rejection; REJ). Spontaneous tolerance induction is associated with increased interferon-gamma expression, and we examined the role of the interferon-gamma-inducible immunomodulatory enzyme indoleamine dioxygenase (IDO) in this model. On day 3 after transplantation, IDO expression in the spleen of TOL recipients was significantly greater than in REJ. The B-cell population accounted for this early IDO increase. Intragraft expression of IDO increased to the same extent in both TOL and REJ. IDO inhibition for 7 days after transplantation reduced survival, but did not cause acute rejection of the liver in the TOL model. In conclusion, the differential IDO expression by B lymphocytes in the spleen of TOL recipients is not critical for preventing acute rejection.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Lam, Vincent W T
%A Taylor, Claire F
%A Laurence, Jerome M
%A Wang, Chuanmin
%A Sharland, Alexandra F
%A McCaughan, Geoffrey W
%A Hodgkinson, Suzanne
%A Allen, Richard D M
%A Hall, Bruce M
%A Bishop, G Alex
%T Heart allograft acceptance induced by anti-CD3 antibody in high-responder rats: Effect on foxp3 and cytokine expression and graft infiltration.
%B Transplant Immunology
%D 2008
%C Netherlands
%I Elsevier BV
%V 19
%N 1
%P 20-24
%@ 0966-3274
%X The ability of anti-T cell monoclonal antibody G4.18 and polyclonal anti-lymphocyte serum (ALS) to induce long-term graft survival was examined in a high-responder rat heart transplant model. Heterotopic heart allografts were performed from PVG rat strain donors to high-responder Lewis recipients. Immunosuppressive properties of G4.18 and ALS were investigated by immunohistochemistry and PCR analysis. Untreated graft rejection was 8.5 days while treatment with 1 ml ALS prolonged survival to 11.5 days (p=0.01). Treatment with 7 mg/kg G4.18 on days 1 and 3 prolonged survival to >100 days (p=0.002 vs. control and p=0.002 vs. ALS) but did not induce tolerance. Acceptance was associated with marked inhibition of cellular infiltration and inflammatory cytokine expression and only a brief, slight increase in Foxp3:T cell ratio in the graft and no increase in the spleen. In conclusion, G4.18 treatment led to long-term heart transplant survival associated with marked inhibition of early inflammation. Failure to develop tolerance was associated with a lack of early accumulation of Foxp3 cells in the graft or spleen.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A Benseler, Volker
%A Bowen, David G
%A Bouillet, Philippe
%A Strasser, Andreas
%A O'Reilly, Lorraine
%A d'Avigdor, William
%A Bishop, Alex G
%A McCaughan, Geoffrey W
%A Bertolino, Patrick
%T Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death.
%B Gastroenterology
%D 2008
%C INDEPENDENCE SQUARE
%I W B Saunders Co
%V 135
%N 3
%P 989-97
%@ 0016-5085
%X Chronic infections by hepatotropic viruses such as hepatitis B and C are generally associated with an impaired CD8 T-cell immune response that is unable to clear the virus. The liver is increasingly recognized as an alternative site in which primary activation of CD8 T cells takes place, a property that might explain its role in inducing tolerance. However, the molecular mechanism by which intrahepatically activated T cells become tolerant is unknown. Here, we investigated the phenotype and fate of na??ve CD8 T cells activated by hepatocytes in vivo.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Bishop, G Alex
%A Williams, Rohan B H
%T Screening liver transplant patients for tolerance.
%B Hepatology (Baltimore, Md.)
%D 2008
%C United States
%I John Wiley & Sons Inc.
%V 48
%N 6
%P 2082-4
%@ 0270-9139
%X 
%Z FOR Codes: 110307


%0 Book Section
%A Kanatani, T
%A Lanzetta, Marco
%A Bishop, Alex
%T Indefinite Survival and Functional Recovery of Limb Allografts in Rodents
%B Hand Transplantation
%D 2007
%C Italy
%I Springer
%V 
%N 
%P 41-46
%@ 978-88-470-0373-6
%E Lanzetta, Marco
%E Dubernard, Jean-Michel
%X 
%Z FOR Codes: 110323


%0 Book Section
%A Lanzetta, Marco
%A Kubitskiy, A
%A Bishop, Alex
%A Li, J
%A McCaughan, Geoffrey
%T Simultaneous Vascularised Bone Marrow Transplantation to Promote Acceptance of Limb Allografts
%B Hand Transplantation
%D 2007
%C Italy
%I Springer
%V 
%N 
%P 57-59
%@ 978-88-470-0373-6
%E Lanzetta, Marco
%E Dubernard, Jean-Michel
%X 
%Z FOR Codes: 110323


%0 Journal Article
%~ PubMed
%A Kubitskiy, Alexander
%A Li, Jian
%A Lanzetta, Marco
%A Owen, Earl
%A McCaughan, Geoffrey W
%A Bishop, G Alex
%T Simultaneous vascularized bone marrow transplantation to promote acceptance of hind limb allografts and its effects on central and peripheral chimerism.
%B Transplantation
%D 2007
%C United States
%I Lippincott Williams & Wilkins, Inc.
%V 83
%N 9
%P 1273-1276
%@ 0041-1337
%X Administration of donor bone marrow (BM) cells can improve the outcome of transplantation. The ability of donor vascularized bone marrow transplantation (VBM) to provide an ongoing source of donor cells and improve survival in a rigorous rat model of hind limb transplantation (HLTX) was investigated. HLTX were performed between Brown Norway (BN) donors and Lewis recipients in three groups: HLTX; HLTX plus intravenous donor BM cells and HLTX plus simultaneous VBM transplantation. Animals received 12 weeks triple immunosuppression. Survival was compared at 4 months and donor chimerism was evaluated. Simultaneous VBM transplantation led to slight but nonsignificant prolongation of survival (P=0.056). Donor cells in the VBM were eventually replaced by recipient and there was no long-term increase in chimerism. Few donor cells were observed in thymus. Simultaneous VBM transplantation showed a trend for improved survival of HLTX however the VBM failed to provide a sustained increase in chimerism.
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Benseler, Volker
%A McCaughan, Geoffrey W
%A Schlitt, Hans J
%A Bishop, G Alex
%A Bowen, David G
%A Bertolino, Patrick
%T The liver: a special case in transplantation tolerance.
%B Seminars in liver disease
%D 2007
%C United States
%I Thieme Medical Publishers
%V 27
%N 2
%P 194-213
%@ 0272-8087
%X Liver transplants are not often rejected in patients weaned from immunosuppression and are spontaneously accepted in some animal models. We review past and recent findings of liver transplantation and propose a unified model in which several mechanisms act in concert to induce and maintain tolerance in both naïve and effector T cell compartments. First, passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive naïve T cells. Second, antigen-specific activation and subsequent deletion of naïve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Other mechanisms such as microchimerism and migration of donor dendritic cells to the thymus may play a predominant role in maintaining tolerance, and soluble major histocompatibility complex molecules, donor peptides, and regulatory T cells may participate in the induction and maintenance phases. Thus, the major challenge in liver transplantation will be to favor these tolerogenic processes while developing strategies that specifically inhibit alloreactive memory T cells.
%Z FOR Codes: 110703


%0 Journal Article
%~ Isi
%A Sadeghi, A.
%A Xiao, C.
%A Sharland, A. F.
%A Allen, R. D. M.
%A McCaughan, G. W.
%A Bishop, G. A.
%T Cytokine common gamma chain expression and its relation to liver transplant tolerance and rejection in a rat model.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A27-A28
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Wang, C. M.
%A Cordoba, S.
%A Bertolino, P.
%A Alexander, S.
%A Wu, M.
%A Allen, R.
%A McCaughan, G.
%A Bishop, G. A.
%T Examination of the immune mechanism of spontaneous tolerance of renal allografts in a mouse model.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A29-A30
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ PubMed
%A Cordoba, Shaun P
%A Wang, Chuanmin
%A Williams, Rohan
%A Li, Jian
%A Smit, Lynn
%A Sharland, Alexandra
%A Allen, Richard
%A McCaughan, Geoffrey
%A Bishop, Alex
%T Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction.
%B Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
%D 2006
%C United States
%I John Wiley & Sons, Inc.
%V 12
%N 4
%P 636-43
%@ 1527-6465
%X This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta-analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty-six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT-1, IRF-1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT-PCR. The results were compared to two published high-throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT-1 and IRF-1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT-1, IRF-1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT-1/IRF-1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism.
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Lam, V.
%A Laurence, J.
%A Sharland, A.
%A McCaughan, G.
%A Hodgkinson, S.
%A Hall, B.
%A Allen, R.
%A Bishop, A.
%T Induction of long-term cardiac allograft survival using anti-lymphocyte antibodies in the rat model.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A27-A27
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Kanatani, T.
%A Lanzetta, M.
%A Matsumoto, T.
%A Fujioka, H.
%A Kurosaka, M.
%A Bishop, G. A.
%T Long-term acceptance of fully MHC-mismatched limb allografts after a short course of anti-alpha beta-T cell receptor monoclonal antibody and FK506.
%B Immunology and Cell Biology
%D 2006
%C Australia
%I Blackwell Publishing Asia
%V 84
%N 3
%P A30-A31
%@ 0818-9641
%X 
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Benseler, V.
%A Cordoba, S.
%A Wang, C.
%A Zvolynska, A.
%A Sharland, A.
%A Shlitt, H.
%A McCaughan, G.
%A Allen, R.
%A Bishop, G. A.
%T Microarray analysis of spontaneously tolerant compared to rejecting rat liver allografts.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A31-A32
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Buchanan, A.
%A Wang, C. M.
%A Tran, G.
%A Hodgkinson, S.
%A Hall, B.
%A McCaughan, G.
%A Allen, R.
%A Bishop, G. A.
%T Role of IL-4 in rat liver allograft rejection.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A28-A28
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Laurence, J.
%A Wang, C. M.
%A Park, T.
%A Vis, A.
%A Allen, R. D. M.
%A Bishop, G. A.
%A Sharland, A. F.
%T Role of indoleamine dioxygenase (IDO) in rat models of transplantation rejection and tolerance.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A30-A30
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Kubitskiy, A.
%A Lanzetta, M.
%A Owen, E.
%A McCaughan, G. W.
%A Bishop, G. A.
%T Simultaneous vascularised bone marrow transplantation to promote acceptance of hind limb allografts.
%B Immunology and Cell Biology
%D 2006
%C Australia
%I Blackwell Publishing Asia
%V 84
%N 3
%P A30-A30
%@ 0818-9641
%X 
%Z FOR Codes: 110708


%0 Journal Article
%~ Isi
%A Cordoba, S.
%A Wang, C.
%A Sharland, A.
%A McCaughan, G.
%A Allen, R.
%A Bishop, G. A.
%T Transcriptomics of tolerant and rejecting renal allografts.
%B Immunology and Cell Biology
%D 2006
%C UK
%I Nature Publishing Group
%V 84
%N 3
%P A2-A2
%@ 0818-9641
%X 
%Z FOR Codes: 110708