Home About us Contact
|
Home About us Contact | ||
|
|
||
Heart Allografts (heart + allograft)
Selected AbstractsRole of TNF, in Early Chemokine Production and Leukocyte Infiltration into Heart AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010D. Ishii The acute phase cytokines IL-1,, IL-6 and TNF, are produced early during inflammatory processes, including ischemia-reperfusion. The appearance and role of these cytokines in the early inflammation following reperfusion of grafts remain poorly defined. This study investigated the role of TNF, in the induction of early leukocyte infiltration into vascularized heart allografts. TNF, and IL-6 mRNA levels reached an initial peak 3 h posttransplant and a second peak at 9,12 h with equivalent levels in iso- and allografts. A single dose of anti-TNF, mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T-cell infiltration into allografts. Anti-TNF, mAb also extended graft survival from 8.6 ± 0.6 days to 14.1 ± 0.8 days. When assessed on day 7 posttransplant, the number of donor-reactive CD8 T cells producing IFN-, in the spleen was reduced almost 70% in recipients treated with anti-TNF, mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNF, and anti-CD154 mAb delayed rejection to day 32 and resulted in long-term (>80 days) survival of 40% of the heart allografts. These data implicate TNF, as an important mediator of early inflammatory events in allografts that undermine graft survival. [source] Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft ToleranceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009W. Ge The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. We investigated whether MSCs could prolong allograft survival. Treatment involving infusion of MSCs into BALB/c recipients 24 hours after receiving a heart allograft from a C57BL/6 donor significantly abated rejection and doubled graft mean survival time compared to untreated recipients. Furthermore, combination therapy of MSCs and low-dose Rapamycin (Rapa) achieved long-term heart graft survival (>100 days) with normal histology. The treated recipients readily accepted donor skin grafts but rejected third-party skin grafts, indicating the establishment of tolerance. Tolerant recipients exhibited neither intragraft nor circulating antidonor antibodies, but demonstrated significantly high frequencies of both tolerogenic dendritic cells (Tol-DCs) and CD4+CD25+Foxp3+T cells in the spleens. Infusion of GFP+C57BL/6-MSCs in combination with Rapa revealed that the GFP-MSCs accumulated in the lymphoid organs and grafts of tolerant recipients. Thus, engraftment of infused MSCs within the recipient's lymphoid organs and allograft appeared to be instrumental in the induction of allograft-specific tolerance when administered in combination with a subtherapeutic dose of Rapamycin. This study supports the clinical applicability of MSCs in transplantation. [source] Quilty Effect Has the Features of Lymphoid Neogenesis and Shares CXCL13,CXCR5 Pathway With Recurrent Acute Cardiac RejectionsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2007E. Di Carlo Quilty effect (QE) is a frequent, yet enigmatic feature of cardiac allograft, since it is apparently devoid of clinical significance, though its association with acute (A) rejection (R) is strongly suspected. It was observed in 126/379 biopsies from 22 patients during the first posttransplant year. Most grade (G)2R biopsies displayed a concomitant QE. The following features typical of QE were identified: (a) focal angiogenesis and lymphangiogenesis associated with bFGF, VEGF-C and VEGF-A expression, (b) marked infiltrate of CD4+T and CD20+B followed by CD8+T lymphocytes arranged around PNAd+HEV-like vessels. Most QE appear as distinct B,T-cell-specific areas with lymphoid follicles sometimes endowed with germinal center-like structures containing VCAM-1+CD21+FDC and CD68+macrophages, which frequently expressed CXCL13. These cells were also found in mantle-like zones, where small lymphocytes expressed CXCR5, otherwise in the whole area of not clustered lymphoid aggregates. CXCL13 was also expressed, in association with CD20+B lymphocyte recruitment, in G2R biopsies obtained from patients with recurrent AR. QE has features of a tertiary lymphoid tissue suggesting an attempt, by the heart allograft, to mount a local response to a persistent alloantigen stimulation resulting in aberrant CXCL13 production, as also occurs in recurrent AR. CXCL13-CXCR5 emerge as a common molecular pathway for QE and recurrent episodes of AR. [source] Administration of dendritic cells modified by RNA interference prolongs cardiac allograft survivalMICROSURGERY, Issue 4 2007Jianbin Xiang M.D. Systemic administration of immature donor-dendritic cells (DC) that are deficient in co-stimulatory molecules delays the onset of allograft rejection. However, it is not easy to control culture condition and guarantee that the administered DC are in the immature stages, which obviously affects their therapeutic effect. In this study, we attempted to inhibit expression of CD86 on DC using an RNA interference technology. The function of CD86low DC was determined by the influence on their capacity to stimulate T cell proliferation and by the effect of DC systemic administration on survival of cardiac allografts. CD86low DC stimulated low T cell proliferative responses in vitro and administration of CD86low DC prolonged survival of heart allografts in vivo. These results suggest that RNA interference is a useful approach to modify DC function, which has potentials for clinical application. © 2007 Wiley-Liss, Inc. Microsurgery 2007. [source] Electroporation-mediated interleukin-10 overexpression in skeletal muscle reduces acute rejection in rat cardiac allograftsTHE JOURNAL OF GENE MEDICINE, Issue 2 2006Reza Tavakoli Abstract Objectives Human interleukin 10 (hIL-10) may reduce acute rejection after organ transplantation. Our previous data shows that electroporation-mediated transfer of plasmid DNA to peripheral muscle enhances gene transduction dramatically. This study was designed to investigate the effect of electroporation-mediated overexpression of hIL-10 on acute rejection of cardiac allografts in the rat. Methods The study was designed to evaluate the effect of hIL-10 gene transfer on (a) early rejection pattern and (b) graft survival. Gene transfer was achieved by intramuscular (i.m.) injection into the tibialis anterior muscle of Fischer (F344) male recipients followed by electroporation 24 h prior to transplantation. Heterotopic cardiac transplantation was performed from male Brown Norway rat to F344. Four groups were studied (n = 6). Treated animals in groups B1 and B2 received 2.5 µg of pCIK hIL-10 and control animals in groups A1 and A2 distilled water. Graft function was assessed by daily palpation. Animals from group A1 were sacrificed at the cessation of the heart beat of the graft and those in group B1 were sacrificed at day 7; blood was taken for ELISA measurement of hIL-10 and tissue for myeloperoxidase (MPO) measurement and histological assessment. To evaluate graft survival, groups A2 and B2 were sacrificed at cessation of the heart beat of the graft. Results Histological examination revealed severe rejection (IIIB-IV) in group A1 in contrast to low to moderate rejection (IA-IIIA) in group B1 (p = 0.02). MPO activity was significantly lower in group B1 compared to group A1 (18 ± 7 vs. 32 ± 14 mU/mg protein, p = 0.05). Serum hIL-10 levels were 46 ± 13 pg/ml in group B1 vs. 0 pg/ml in group A1. At day 7 all heart allografts in the treated groups B1 and B2 were beating, whereas they stopped beating at 5 ± 2 days in groups A1 and A2 vs. 14 ± 2 days in group B2 (p = 0.0012). Conclusions Electroporation-mediated intramuscular overexpression of hIL-10 reduces acute rejection and improves survival of heterotopic heart allografts in rats. This study demonstrates that peripheral overexpression of specific genes in skeletal muscle may reduce acute rejection after whole organ transplantation. Copyright © 2006 John Wiley & Sons, Ltd. [source] In Vivo Function of Immune Inhibitory Molecule B7-H4 in Alloimmune ResponsesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010K. Yamaura B7 ligands deliver both costimulatory and coinhibitory signals to the CD28 family of receptors on T lymphocytes, the balance between which determines the ultimate immune response. Although B7-H4, a recently discovered member of the B7 family, is known to negatively regulate T cell immunity in autoimmunity and cancer, its role in solid organ allograft rejection and tolerance has not been established. Targeting the B7-H4 molecule by a blocking antibody or use of B7-H4,/, mice as recipients of fully MHC-mismatched cardiac allografts did not affect graft survival. However, B7-H4 blockade resulted in accelerated allograft rejection in CD28-deficient recipients. B7-1/B7-2-double-deficient recipients are truly independent of CD28/CTLA-4:B7 signals and usually accept MHC-mismatched heart allografts. Blockade of B7-H4 in these mice also precipitated rejection, demonstrating regulatory function of this molecule independent of an intact CD28/CTLA-4:B7 costimulatory pathway. Accelerated allograft rejection was always accompanied by increased frequencies of alloreactive IFN-,-, IL-4- and Granzyme B-producing splenocytes. Finally, intact recipient, but not donor, B7-H4 is essential for prolongation of allograft survival by blocking CD28/CTLA4:B7 pathway using CTLA4-Ig. These data are the first to provide evidence of the regulatory effects of B7-H4 in alloimmune responses in a murine model of solid organ transplantation. [source] Regulatory T Cells Are Critical to Tolerance Induction in Presensitized Mouse Transplant Recipients Through Targeting Memory T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010W. Ge Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40+CD44hieffector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (,-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, ,-OX40L was added to the combined treatment protocol of LF15,0195 (LF) and anti-CD45RB (,-CD45RB) mAb,a protocol that induced heart allograft tolerance in non-presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor-specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4+CD25+Foxp3+ T regulatory cells (Tregs). Of note, CD25+ T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor-primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance. [source] Role of TNF, in Early Chemokine Production and Leukocyte Infiltration into Heart AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010D. Ishii The acute phase cytokines IL-1,, IL-6 and TNF, are produced early during inflammatory processes, including ischemia-reperfusion. The appearance and role of these cytokines in the early inflammation following reperfusion of grafts remain poorly defined. This study investigated the role of TNF, in the induction of early leukocyte infiltration into vascularized heart allografts. TNF, and IL-6 mRNA levels reached an initial peak 3 h posttransplant and a second peak at 9,12 h with equivalent levels in iso- and allografts. A single dose of anti-TNF, mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T-cell infiltration into allografts. Anti-TNF, mAb also extended graft survival from 8.6 ± 0.6 days to 14.1 ± 0.8 days. When assessed on day 7 posttransplant, the number of donor-reactive CD8 T cells producing IFN-, in the spleen was reduced almost 70% in recipients treated with anti-TNF, mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNF, and anti-CD154 mAb delayed rejection to day 32 and resulted in long-term (>80 days) survival of 40% of the heart allografts. These data implicate TNF, as an important mediator of early inflammatory events in allografts that undermine graft survival. [source] An Immunomodulatory Role for Follistatin-Like 1 in Heart Allograft TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2008J. B. Le Luduec Donor-specific tolerance to heart allografts in the rat can be achieved by donor-specific blood transfusions (DST) before transplantation. We have previously reported that this tolerance is associated with strong leukocyte infiltration, and that host CD8+ T cells and TGF, are required. In order to identify new molecules involved in the induction phase of tolerance, we compared tolerated and rejected heart allografts (suppressive subtractive hybridization) 5 days after transplantation. We identified overexpression of Follistatin-like 1 (FSTL1) transcript in tolerated allografts compared to rejected allografts or syngeneic grafts. We show that FSTL1 is overexpressed during both the induction and maintenance phase of tolerance, and appears to be specific to the tolerance model induced by DST. Analysis of graft-infiltrating cells revealed predominant expression of FSTL1 in CD8+ T cells from tolerated grafts, and depletion of these cells prior to transplantation abrogated FSTL1 expression and heart allograft survival. Moreover, overexpression of FSTL1 by adenovirus gene transfer in vivo significantly prolonged allograft survival in association with inhibition of the proinflammatory cytokines, IL6, IL17 A and IFN,. Taken together, these results suggest that FSTL1 could be an active component of the mechanisms mediating heart allograft tolerance. [source] Hyperhomocyst(e)inemia Induces Accelerated Transplant Vascular Sclerosis in Syngeneic and Allogeneic Rat Cardiac TransplantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2002Judith W. Cook Chronic rejection (CR) and transplant vascular sclerosis (TVS) cause the majority of graft failures in cardiac transplantation. Hyperhomocyst(e)inemia [hH(e)] is associated with human TVS without a proven causal relationship. This study investigated the effect of hH(e) on graft survival and TVS in allogeneic and syngeneic rat cardiac transplants. Lewis recipients of heterotopic F344 heart allografts, received normal or hH(e)-inducing (,folate, ,methionine) diets {controls: syngeneic transplanted [± hH(e), + CsA] and nontransplanted rats [± hH(e), ± CsA]}. Serial plasma homocyst(e)ine [H(e)] levels were measured. TVS was assessed in clinically rejected grafts and a subset of pre-rejection normal diet allografts (day 64) (neointimal index, NI). The hH(e) diet elevated plasma H(e) levels. When compared with normal diet controls (n = 9), hH(e) diet allografts (n = 9) had decreased time to onset of CR (40 ± 9 vs. 72 ± 10 d, p = 0.02), and graft failure (64 ± 10 vs. 107 ± 12 d, p = 0.009). hH(e) diet allografts at rejection (n = 9, 64 d) had more severe TVS (NI = 68 ± 2) than both time-matched normal diet allografts (NI = 49 ± 6, n = 8, 64 d, p <,0.001) and normal diet allografts at rejection (NI = 58 ± 5, n = 9, 107 d, p = 0.007). hH(e) induced TVS in syngeneic grafts (NI = 50 ± 3, n = 10 vs. NI = 5 ± 3, n = 10, 130 d, p <,0.001). hH(e) accelerated rejection and increased the severity of TVS in allogeneic cardiac transplants, and induced TVS in syngeneic cardiac transplants. [source] Different Mechanisms of Cardiac Allograft Rejection in Wildtype and CD28-deficient MiceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2001Gregory L. Szot Although CD28 blockade results in long-term cardiac allograft survival in wildtype mice, CD28-deficient mice effectively reject heart allografts. This study compared the mechanisms of allogeneic responses in wildtype and CD28-deficient mice. Adoptive transfer of purified CD28-deficient T cells into transplanted nude mice resulted in graft rejection. However, this model demonstrated that the allogeneic T cell function was severely impaired when compared with wildtype T cells, despite similar survival kinetics. Cardiac allograft rejection depended on both CD4+ and CD8+ T cell subsets in CD28-deficient mice, whereas only CD4+ T cells were necessary in wildtype recipients. These results suggested that CD8+ T cells were more important in CD28-deficient than wildtype mice. In addition to the CD8+ T cell requirement, allograft rejection in CD28-deficient mice was dependent on a sustained presence of CD4+ T cells, whereas it only required the initial presence of CD4+ T cells in wildtype mice. Taken together, these data suggest that CD4+ T cells from CD28-deficient mice have impaired responses to alloantigen in vivo, thus requiring long-lasting cooperation with CD8+ T cell responses to facilitate graft rejection. These results may help to explain the failure to promote graft tolerance in some preclinical and clinical settings. [source] | ||||||||||