[Genetic alterations in biliary tract carcinoma].
Explore the source record for details and available documents.
Biliary Tract Neoplasms↗
Biomedical subjects
Masayuki Sho
Publications and source records attributed to Masayuki Sho.
A potent antiangiogenic factor, endostatin prevents the development of asthma in a murine model.
BACKGROUND: Clinical studies suggest a role for angiogenesis in the development and persistence of chronic asthma, but whether angiogenic mediators contribute to acute asthma has not been fully studied. OBJECTIVE: The aim of this study was to investigate a role of vascular endothelial growth factor (VEGF), a major angiogenic and proinflammatory mediator, in allergen-induced acute asthma and to determine whether endostatin/Fc, a potent antiangiogenic factor can attenuate allergic airway responses. METHODS: We sensitized BALB/c mice with ovalbumin. We measured serum VEGF and examined immunoreactive VEGF around the airways 48 hours after the last challenge with either aerosolized PBS or ovalbumin once per day for 3 days. We also treated ovalbumin-sensitized mice with either endostatin/Fc or control fusion protein at the time of challenge with ovalbumin. We analyzed allergic airway responses 48 hours after the last ovalbumin challenge. RESULTS: Ovalbumin challenge induced immunolocalization of numerous VEGF-positive cells around airways and increased serum VEGF levels. Treatment with endostatin/Fc inhibited the airway hyperresponsiveness, pulmonary allergic inflammation, production of ovalbumin-specific IgE, and lung inflammatory mediators. Both VEGF-dependent and independent mechanisms are indicated by results using antibody blockade of VEGF receptors, which caused decreased allergic pulmonary inflammation but did not alter airway hyperresponsiveness or serum IgE levels. CONCLUSION: These data demonstrate for the first time that recombinant endostatin can prevent the development of asthma features in a mouse model and suggest that this class of agents merits further study as novel therapeutics for asthma.
Angiogenesis Inhibitors↗
Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo.
BACKGROUND: We have recently reported that vascular endothelial growth factor (VEGF) functions as a proinflammatory cytokine to regulate the trafficking of leukocytes into allografts in the early posttransplant period. VEGF binds two major VEGF receptors: VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Here, we wished to investigate the expression and function of VEGF receptors in the process of acute allograft rejection in vivo. METHODS: We performed fully MHC-mismatched C57BL/6 (H-2b) into BALB/c (H-2d) vascularized heterotopic murine cardiac transplants and we examined the expression of VEGF and VEGF receptors by immunohistochemistry during acute allograft rejection. Next, we treated mice with specific neutralizing monoclonal antibodies against murine VEGFR-1 and VEGFR-2 and examined their effect on the development of acute allograft rejection by histology and by analysis of graft survival. The intragraft expression of cytokines and chemokines were also evaluated by quantitative real-time PCR analysis. RESULTS: The expression of VEGF, VEGFR-1 and VEGFR-2 were significantly up-regulated during allograft rejection as compared to isografts. Administration of either anti-VEGFR-1 or anti-VEGFR-2 alone failed to inhibit allograft rejection. However, coadministration of both antibodies together inhibited leukocyte infiltration of allografts and prolonged allograft survival. Furthermore, the effect of VEGFR blockade was associated with the downregulation of intragraft cytokine and chemokine expression. CONCLUSIONS: Our data suggest that VEGF-VEGFR interactions function in the alloimmune response in vivo. Targeting VEGFRs may represent a novel therapy to protect allografts following clinical transplantation.
Acute Disease↗
Requirements for induction and maintenance of peripheral tolerance in stringent allograft models.
Peripheral tolerance can be achieved in many but not all murine allograft models. The requirements for controlling more aggressive immune responsiveness and generating peripheral tolerance in stringent allograft models are unknown. Understanding these requirements will provide insight toward ultimately achieving tolerance in humans, which are also resistant. We now demonstrate that the combination of donor-specific transfusion, anti-CD45RB, and anti-CD154 uniformly achieves >90-d survival of BALB/c skin allografts on C57BL/6 recipients. Recipients exhibit marked hyporesponsiveness to alloantigen in vitro. In distinct contrast to less rigorous models, engraftment remains absolutely dependent on cytotoxic T lymphocyte antigen 4 signaling, even after grafts are healed, suggesting that prolonged engraftment cannot simply be attributed to more effective depletion of alloreactive T cells but is actively maintained by regulation. Concordantly, we show that both CD4 and CD8 regulatory cells are required and can transfer donor-specific tolerance to naïve recipients. Nonetheless, most recipients ultimately develop gradual graft loss (median survival time = 140 d), suggesting that alloreactive cells emerging from the thymus eventually overwhelm regulatory capacity. In agreement, adding thymectomy to the regimen results in permanent engraftment (>250 d) and donor-specific tolerance not observed previously in this model. These results highlight the potency of both CD4 and CD8 regulatory cells but also suggest that in stringent settings, regulatory T cell longevity and capacity for infectious tolerance compete with prolonged graft immunogenicity and thymic output. These results provide insight into the mechanisms of tolerance in stringent models and provide a rational basis for innovative tolerogenic strategies in humans.
Animals↗
A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.
BACKGROUND: Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. METHODS: Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. RESULTS: Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. CONCLUSIONS: Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.
Amides↗
Dual role of vascular endothelial growth factor in hepatic ischemia-reperfusion injury.
BACKGROUND: Vascular endothelial growth factor (VEGF), a major angiogenic factor, mediates a variety of disease conditions through promotion of angiogenesis. It also plays a critical role as a potent proinflammatory cytokine in a variety of physiologic and pathologic immune responses. In the present study, we evaluated the expression of VEGF in hepatic warm ischemia-reperfusion (I/R) injury and examined the effect of recombinant human (rh)VEGF administration in an established murine model. METHOD: The expression of VEGF in the liver was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry during I/R injury using 70% partial hepatic ischemia model. The effect of rhVEGF administration on I/R injury was evaluated by measuring liver function and histology. In addition, local inducible nitric oxide synthase (iNOS) and endothelial NO synthase expressions were examined to address the underlying mechanisms. RESULTS: The local expression of VEGF was significantly up-regulated at 2 hours after reperfusion after 60 minutes of ischemia compared with that in the naive liver. VEGF was expressed predominantly in CD11b+ cells infiltrating into the ischemic liver. The administration of rhVEGF had a significant protective effect on ischemic injury in the liver. This effect was associated with the up-regulation of iNOS expression in the rhVEGF-treated liver. CONCLUSION: We demonstrate a dual role of VEGF in hepatic warm I/R injury. Although endogenous VEGF is expressed and functional to initiate hepatic I/R injury, exogenous rhVEGF has a beneficial effect on the ischemic liver. These data may provide new insights into the role of VEGF as well as pathophysiology of hepatic I/R injury.
Animals↗
Role of the ICOS-B7h costimulatory pathway in the pathophysiology of chronic allograft rejection.
BACKGROUND: Inducible costimulator (ICOS) is the third member of the CD28 superfamily and has a unique role in T cell activation and function. Recent studies indicated that the ICOS-B7h pathway plays an important role in alloimmune responses. We further investigated the role of the ICOS pathway in the pathologic process of chronic rejection in vivo. METHODS: An established major histocompatibility complex class II disparate cardiac transplantation model was used. We treated mice with a blocking anti-B7h monoclonal antibody (mAb) either in the initiation phase (early blockade) or in the progression phase (delayed blockade) of disease. In addition, some mice received mAb in the entire period (whole blockade). At 6 weeks after transplantation, cardiac grafts were evaluated by histopathologic analysis in terms of vasculopathy, fibrosis, and cellular infiltration. The intragraft expressions of cytokines and chemokines were also examined by quantitative real-time polymerase chain reaction analysis. RESULTS: Early blockade of the ICOS-B7h pathway did not show any protective effect on chronic allograft rejection compared with untreated controls. In contrast, delayed blockade significantly inhibited the development of vasculopathy, fibrosis, and cellular infiltration (P=0.043, P=0.004, and P=0.03 vs. untreated control, respectively). Interestingly, whole blockade did not prevent the chronic rejection process. Furthermore, the inhibitory effect of delayed ICOS blockade on chronic rejection was associated with down-regulation of local intragraft expression of several cytokines and chemokines. CONCLUSIONS: These data suggest that the ICOS-B7h pathway is critical in the activation of effector/memory T cells that are necessary for the progression of chronic rejection and provide the rationale to develop novel and specific therapies to prevent this process.
Animals↗
Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer.
PURPOSE: The negative regulatory programmed death-1/programmed death-1 ligand (PD-1/PD-L) pathway in T-cell activation has been suggested to play an important role in tumor evasion from host immunity. In this study, we investigated the expression of PD-L1 and PD-L2 in human esophageal cancer to define their clinical significance in patients' prognosis after surgery. EXPERIMENTAL DESIGN: PD-L1 and PD-L2 gene expression was evaluated in 41 esophagectomy patients by real-time quantitative PCR. The protein expression was also evaluated with newly generated monoclonal antibodies that recognize human PD-L1 (MIH1) and PD-L2 (MIH18). RESULTS: The protein and the mRNA levels of determination by immunohistochemistry and real-time quantitative PCR were closely correlated. PD-L-positive patients had a significantly poorer prognosis than the negative patients. This was more pronounced in the advanced stage of tumor than in the early stage. Furthermore, multivariate analysis indicated that PD-L status was an independent prognostic factor. Although there was no significant correlation between PD-L1 expression and tumor-infiltrating T lymphocytes, PD-L2 expression was inversely correlated with tumor-infiltrating CD8(+) T cells. CONCLUSIONS: These data suggest that PD-L1 and PD-L2 status may be a new predictor of prognosis for patients with esophageal cancer and provide the rationale for developing novel immunotherapy of targeting PD-1/PD-L pathway.
Aged↗
CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.
The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.
Acute Disease↗
Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice.
Prostaglandin E2 (PGE2) mediates a variety of innate and adaptive immunity through four distinct receptors: EP1-EP4. It has been suggested that each EP plays a unique and pivotal role in various disease conditions. We investigated the pathophysiological role of EP receptors in hepatic ischemia/reperfusion (I/R) injury. In this study, a 70% hepatic ischemic model was used in male C57BL/6 mice. Selective EP agonists were used to clarify the function of each PGE2 receptor in I/R injury. Although all four receptors were expressed in the naïve liver, EP4 expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EP4 agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EP4 agonist downregulated the local expressions of several proinflammatory cytokines, chemokines, and adhesion molecules in the early phase of reperfusion. In contrast, it augmented the local expression of an anti-inflammatory cytokine, interleukin 10. Additionally, the neutrophil accumulation was also inhibited by EP4 agonist treatment. Finally, to confirm the therapeutic efficacy of the EP4 agonist in hepatic I/R injury, the nonischemic shunt liver was removed after 120 minutes of ischemia, resulting in the death of 86% of control mice within 48 hours. In sharp contrast, 80% of mice treated with the EP4 agonist survived. In conclusion, the PGE2-EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury.
Alanine Transaminase↗
Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
BACKGROUND: Establishment of hematopoietic chimerism is the most stable strategy for donor-specific tolerance. Safer pretreatment regimens are needed for clinical application. We evaluated the efficacy of a simple protocol using cyclophosphamide (CYP) on induction of chimerism and organ transplant tolerance across major histocompatibility complex (MHC) barriers in the rat. MATERIALS AND METHODS: Bone marrow cells from BN (RT1(n)) donors were infused to LEW (RT1(l)) recipients on day 0 after a single injection of CYP at various doses on day -1. Donor-derived hematopoietic chimerism was evaluated by flowcytometry. The recipients received BN or third party (BUF) heart allografts on day 100. RESULTS: While pretreatment with 200 mg/kg of CYP induced high levels of hematopoietic chimerism, six of eight recipients died of severe graft-versus-host-disease (GVHD). CYP at dose of 150 mg/kg induced 36.5 +/- 24.1% of donor-derived chimerism on day 10, and sustained macrochimerism was seen until day 100 without GVHD. Pretreatment with 100 mg/kg of CYP resulted in only transient chimerism (4.8 +/- 5.2%) which disappeared by day 20. In the recipients with 50 mg/kg of CYP, donor bone marrow cells were rapidly rejected and no chimerism was observed. The recipients with 150 mg/kg of CYP accepted BN heart allografts (>100 days x 5), while rejecting BUF allografts by day 12 (n = 4). BN heart allografts were rejected in the recipients with 100 (MST: 57 days, n = 5) and 50 mg/kg (MST: 7 days, n = 5) of CYP. CONCLUSIONS: A single dose of CYP can induce hematopoietic chimerism across MHC-barriers. The dose of 150 mg/kg seems to be optimal to induce organ transplant tolerance without developing GVHD.
Animals↗
Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer.
p27Kip1 belongs to the family of small polypeptides collectively termed cyclin-dependent kinase inhibitors, which negatively regulate the cell cycle progression. In various human cancers, the reduced p27Kip1 expression correlates well with poor prognosis. Recently, Jab1/CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation. In this study, we investigated the expression of p27Kip1 and Jab1 in 61 cases with pancreatic ductal adenocarcinoma. The p27Kip1 expression was positive in 41% (25/61) of the tumors. Of the 25 positive tumors, 12 cases had p27Kip1 positive expression mainly in the nucleus of the tumor cells, while 13 cases had p27Kip1 in the cytoplasm as well as in the nucleus. Among a variety of clinicopathological factors, only tumor status was inversely correlated with p27Kip1 expression (p=0.019). The Jab1 expression was detected both in the nucleus and the cytoplasm in almost all pancreatic cancer cells. The intensity of Jab1 expression in tumor cells, especially in the cytoplasm, was much stronger than in normal pancreatic ductal epithelial cells. The patients with positive p27Kip1 expression had significantly better prognosis than ones with negative p27Kip1 expression (p=0.008). Furthermore, 12 patients with exclusively nuclear p27Kip1 expression, but not 13 patients with both nuclear and cytoplasmic p27Kip1 expression, had significantly better prognosis than 36 patients with negative p27Kip1 expression (p=0.009). In multivariate survival analysis, localized p27Kip1 expression was an independent prognostic factor (p=0.016). The results of our study suggested that the mislocalization as well as the downregulation of p27Kip1 had significant prognostic value in pancreatic cancer and that Jab1 might play an important role in carcinogenesis of pancreatic cancer. Cell cycle control targeting p27Kip1 might be a promising future therapeutic modality against pancreatic cancer.
Adenocarcinoma↗
Proangiogenic function of CD40 ligand-CD40 interactions.
Angiogenesis is a characteristic component of cell-mediated immune inflammation. However, little is known of the immunologic mediators of angiogenesis factor production. Interactions between CD40 ligand (CD40L) and CD40 have been shown to have pluripotent functions in inflammation, including the production of cytokines, chemokines, as well as the angiogenesis factor, vascular endothelial growth factor (VEGF), by endothelial cells. In this study we found that treatment of cultured human endothelial cells with an anti-CD40 Ab (to ligate CD40) resulted in the expression of several other angiogenesis factors, including fibroblast growth factor-2 and the receptors Flt-1 and Flt-4. To determine the proangiogenic effect of CD40L in vivo, human skin was allowed to engraft on SCID mice for 6 wk. These healed human skins express CD40 on resident endothelial cells and monocyte/macrophages, but not on CD20-expressing B cells. Skins were injected with saline, untransfected murine fibroblasts, or murine fibroblasts stably transfected with human CD40L. We found that the injection of CD40L-expressing cells, but not control cells, resulted in the in vivo expression of several angiogenesis factors (including VEGF and fibroblast growth factor) and a marked angiogenesis reaction. Mice treated with anti-VEGF failed to elicit an angiogenesis reaction in response to injection of CD40L-expressing cells, suggesting that the proangiogenic effect of CD40L in vivo is VEGF dependent. These observations imply that ligation of CD40 at a peripheral inflammatory site is of pathophysiological importance as a mediator of both angiogenesis and inflammation.
Administration, Cutaneous↗
CD45RB-targeting strategies for promoting long-term allograft survival and preventingchronic allograft vasculopathy.
BACKGROUND: CD45RB is a potent immunomodulatory target to achieve long-term allograft survival. We evaluated the in vivo effect of anti-CD45RB monoclonal antibody (mAb) treatment in combination with conventional immunosuppression or costimulatory blockade strategies as a therapeutic modality for future clinical application. METHODS: A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD45RB mAb and conventional immunosuppressive drugs or costimulatory blockade of the CD40/CD154 or B7/CD28 pathway. Chronic rejection was examined histologically for development of chronic allograft vasculopathy. RESULTS: Cyclosporine significantly abrogated the effect of anti-CD45RB therapy. In contrast, rapamycin acted synergistically with anti-CD45RB mAb in promoting long-term allograft survival. CD154 blockade further enhanced the tolerogenic efficacy of anti-CD45RB mAb. These synergistic effects of combination treatments also prevented the development of chronic allograft vasculopathy. CONCLUSION: CD45RB-targeting strategy in combination with the use of rapamycin or costimulatory blockade promotes allograft tolerance and prevents chronic rejection.
Abatacept↗
Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance.
Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.
Animals↗
Allograft rejection in a new allospecific CD4+ TCR transgenic mouse.
The application of TCR transgenic mice to transplantation immunology is hampered by the limited lines available. Recently, we reported CD4+ T cell receptor (TCR) transgenic mice specific for I-Abm12 expressed on B6.C.H-2bm12 mice. Here, we characterized rejection of skin and vascularized cardiac allografts in these mice, which we term ABM (for anti-bm12). In vivo proliferative experiments reveal that all CD4 T cells in ABM mice react to bm12 antigens. Surprisingly, while ABM mice have accelerated (compared to B6 recipients) rejection of bm12 skin allografts, they, like B6 recipients, fail to acutely reject bm12 cardiac allografts. This is not due to lack of immunogenicity of bm12 hearts, as these grafts are acutely rejected by primed ABM recipients, although not by primed B6 recipients. Lastly, long-term surviving bm12 grafts in ABM recipients are relatively free from chronic rejection (compared with B6 recipients), which may be due to skewing of the CD4 repertoire towards direct alloreactivity, and consequent lack of CD4 mediated indirect allorecognition as evidenced by the lack of IgG deposition in those grafts. The results indicate that a complex interplay between responder frequency, priming and repertoire dictates the occurrence, or lack thereof, of acute and chronic rejection.
Animals↗
The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity.
Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility-mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility-mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10-producing cells and an increased frequency of both IFN-gamma- and IL-4-producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription-6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.
Animals↗
Proinflammatory functions of vascular endothelial growth factor in alloimmunity.
Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-gamma synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.
Animals↗