Advance of the role of Aromatic hydrocarbon receptor in immunoregulation related to tryptophan metabolism / 国际外科学杂志

Aromatic hydrocarbon receptor (AhR),an intracellular receptor,contains multiple ligand binding sites.Various ligands of AhR are divided into exogenous and endogenous ligands according to the origination.Different ligands bind and activate AhR,regulating the transcription of downstream target genes,especially CYP1 from Cypcytochrome P450 gene family,which plays an essential role in different pathological problems,as well as in the normal development and function of organism.Kynurenine(Kyn),a key metabolic product of tryptophan (Trp),metabolic products of which are major types of endogenous ligands of AhR,has an impact on adaptive immune by manipulating the polarization and activity of immunocytes.Kyn has been focus for its supressive effect in anti-tumor immunity and raised concern recently for its intriguing role in allograft immunoregulation.Research advances in the role of AhR in immunoregulation related to tryptophan metabolism will be illustrated in this review in detail.

Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice

Objective To investigate the effects of preoperative portal venous injection of donor spleen cells (PVIDSC) and intraperitoneal injection of rapamycin in the acute rejection of cardiac allograft in mice and the underlying mechanisms. Methods Homogenous female B6 mice and BALB/c mice were used as recipients and donors of heart transplantation. These mice were randomly divided into different groups and received PVIDSC alone, rapamycin alone, or PVIDSC and rapamycin combined therapy. In addition, the underlying mechanism was studied by measuring a number of cytokines. Results Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin significantly prolonged the survival of heterotopic cardiac allograft in mice, but had no effects on the survival time of cardiac allografts in mice pre-sensitized by skin grafting. Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin increased the expression of IL-10 and Foxp3 and reduced the expression of INF-. Short-term preoperative administration of rapamycin promotes the expression of CD4

Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice

OBJECTIVE@#To investigate the effects of preoperative portal venous injection of donor spleen cells (PVIDSC) and intraperitoneal injection of rapamycin in the acute rejection of cardiac allograft in mice and the underlying mechanisms.@*METHODS@#Homogenous female B6 mice and BALB/c mice were used as recipients and donors of heart transplantation. These mice were randomly divided into different groups and received PVIDSC alone, rapamycin alone, or PVIDSC and rapamycin combined therapy. In addition, the underlying mechanism was studied by measuring a number of cytokines.@*RESULTS@#Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin significantly prolonged the survival of heterotopic cardiac allograft in mice, but had no effects on the survival time of cardiac allografts in mice pre-sensitized by skin grafting. Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin increased the expression of IL-10 and Foxp3 and reduced the expression of INF-. Short-term preoperative administration of rapamycin promotes the expression of CD4CD25Foxp3 regulator T cells. However, preoperative using alone of rapamycin, or combination of PVIDSC and rapamycin had no effects on the inhibition of proliferation of memory T cells.@*CONCLUSIONS@#Preoperative application of combination of PVIDSC and rapamycin significantly prolonged the survival time of cardiac allografts in mice but not in mice pre-sensitized by skin grafting. This may be explained by the fact that combination of PVIDSC and rapamycin inhibited the cellular immune response and induced the expression of IL-10 from Tr1 cells and CD4CD25FoxP3 regulatory T cells.

Comparative Analyses of Signature Genes in Acute Rejection and Operational Tolerance

Using biomarkers as prediction tools or therapeutic targets can be a valuable strategy in transplantation. Recent studies identified biomarkers of acute rejection (AR) and operational tolerance (TOL) through the application of meta-analysis. In this study, we comparatively analyzed the signature genes in acute rejection and operational tolerance seen in human allogeneic transplantations using massive bioinformatical meta-analysis. To identify the signature genes in opposite immunological conditions, AR and TOL, we first collected the 1,252 gene expression data specifically intended for those circumstances. Then we excluded based on biological cut-values, Principal Component Analysis (PCA) as well as Multi-Dimensional Scaling (MDS). Using differentially expressed genes (DEGs) from meta-analysis, we then applied a ranked scoring system to identify the signature genes of AR and TOL. We identified 53 up-regulated and 32 down-regulated signature genes in acute rejection condition. Among them, ISG20, CXCL9, CXCL10, CCL19, FCER1G, PMSE1, UBD are highly expressed in AR condition. In operational tolerance, we identified 110 up-regulated and 48 down-regulated signature genes. TCL1A, BLNK, MS4A1, EBF1, IGHM are up-regulated in TOL condition. These genes are highly representative of AR or TOL across the different organs such as liver, kidney and heart. Since immune response is the sum of complex biological and molecular dynamics, these signature genes as well as pathway analysis using a systems biology approach could be used to catch the insights of the certain pathways that would be overlooked with the conventional gene-level comparative analysis.

Tolerancia operacional en un receptor pediátrico de trasplante hepático: Caso clínico / Operational tolerance in a pediatric liver transplant recipient: Case report

La tolerancia operacional (ausencia de rechazo del injerto y buena evolución sin inmunosupresión) ha sido objeto de intensa investigación en trasplante hepático pediátrico en los últimos años. La morbimortalidad relacionada con la exposición a drogas inmunosupresoras a largo plazo en estos pacientes es bien conocida. Reportamos un caso de tolerancia operacional de nuestro centro en un receptor pediátrico de trasplante hepático libre de inmunosupresión desde los 16 meses postrasplante luego de una progresiva disminución a partir de su primoinfección asintomática por virus de Epstein-Barr, con buena evolución histológica y clínico-humoral en 22 meses de seguimiento. De acuerdo con nuestro conocimiento, este es el primer caso de tolerancia operacional en un receptor pediátrico de trasplante hepático reportado en nuestro país y creemos que debería profundizarse el estudio de estos pacientes para detectar características que permitan identificar una población potencialmente tolerante en la cual es posible disminuir y suspender la inmunosupresión.

Operational tolerance (absence of allograft rejection and good outcome without immunosuppression) has been object of intense research in pediatric liver transplant in the last years. The morbidity and mortality related to long-term immunosuppressive treatment of these patients are well known. We report a case of operational tolerance of our unit in a pediatric liver transplant recipient who is immunosuppressant-free since 16 month after transplant after progressive withdrawal related to asymptomatic Epstein-Barr virus first infection. He has good histological, clinical and serological outcome after 22 month of follow-up. To our knowledge, this is the first operational tolerance reported case in our country after liver transplant in a pediatric recipient and we believe that the study of these patients is important in order to detect characteristics that allow to identify a potentially tolerant group in which it is possible to withdraw immunosuppressive drugs.

Role of alloreactive T cell in clonal deletion and regulatory T cells in transplant tolerance / 中国免疫学杂志

Objective:To investigate the role of alloreactive T cell in clonal deletion and regulatory T cells ( Treg) in transplant tolerance.Methods:F1 mice were bred by crossing female BALB/c mice and male C57BL/6 mice.Within 24 h,newborn C57BL/6 mice were inoculated with F1 spleen cells via the orbital branch of the anterior facial vein.Six weeks later,the mice were subjected to F1 skin grafting to evaluate their tolerance.Proliferation,flow cytometry and adoptive transfer assay were used to analyze clonal deletion of alloreactive T cells and the expression of CD4+Foxp3+T cells in neonatal treated mice.Results: Newborn C57BL/6 mice injected with F1 splenic cells could induce transplantation tolerance,the level of tolerance was associated with the dose of splenic cells.3×107 splenic cells from F1 mice could induce long-term skin graft acceptance in C57BL/6 mice ,1×107splenic cells significantly prolonged the survival of F1 skin grafts,but the grafts completely rejected within 50 days.The mixed lymphocyte reaction ( MLR) experiment in vivo showed that alloreactive T cell in long-term tolerant mice was deleted completely,but a certain amount of reactive T cells existed in the low-dose group mice.Flow cytometry ( FCM) analysis showed that the expression of CD4+Foxp3+T cell in the high-dose group and low-dose group mice had no obvious difference compared with the naive mice.When alloreactive T-cells were injected into tolerant mice,the skin graft rejection was observed,and Treg cells upregulated in graft-rejected mice.Conclusion:The degree of transplantation tolerance depended on the clonal deletion of alloreactive T cells,instead of on the expression of CD4+Foxp3+Treg cells.CD4+Foxp3+regulatory T cells upregulated in graft rejected mice,which may be served as a negative feedback mechanism to control the intensity of rejection.

Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil / Análise de custo-efetividade: ciclosporina versus tacrolimo para transplante renal no Brasil

OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. However, regimens containing cyclosporine were more cost-effective. .

OBJETIVO Analisar custo-efetividade de regimes terapêuticos com ciclosporina ou tacrolimo cinco anos após transplante renal. MÉTODOS Análise de custo-efetividade com base em dados de coorte histórica 2000-2004, com 2.022 pacientes tratados com ciclosporina ou tacrolimo e pareados 1:1 segundo sexo, idade, tipo e ano de transplante. A sobrevida do enxerto e os custos diretos de cuidados médicos a partir das bases de dados do Sistema Único de Saúde foram utilizados como medida de resultado. RESULTADOS A maioria dos pacientes era do sexo feminino e média de idade de 36,6 anos. O diagnóstico mais frequente de insuficiência renal crônica foi a glomerulonefrite/nefrite (27,7%). Em cinco anos, o grupo tacrolimo obteve uma expectativa de vida média de 3,96 anos de vida ganhos ao custo anual de R$78.360,57 ante 4,05 anos de vida ganhos e de R$61.350,44 para ciclosporina. CONCLUSÕES Após o pareamento, o estudo não mostrou melhor sobrevida dos pacientes com regimes que usam tacrolimo. Além disso, regimes contendo ciclosporina foram mais custo-efetivos. .

Using mice immature dendritic cells to induce the differentiation of allogenic naive T cells in vitro / 中华器官移植杂志

Objective To explore the differentiation of allogeneic naive T cells to regulatory T cells (Tregs) and T helper (TH) 1/2/17 cells by coculture with bone marrow-derivedimmature dendritic cells (irnDC).Method Bone marrow-derived imDC were cultivated from Balb/c mice.Lipopolysaccharide-stimulated DC were harvested as mature dendritic cells (mDC) and unstimulated cells were collected as imDC.Then irnDC or mDC were cocultured with allogeniec naive T cells,respectively.TH1 cytokines [interferon-γ (IFN-γ) and interleukin (IL)-2],TH2 cytokines (IL-4 and IL-10),and TH17 cytokine (IL-17) of co-cultured cells were detected by enzyme linked immunospot assay.CD4+ Forkhead box p3 (FoxP3) + Treg proportion in CD4+ cells in the co-cultured system with IL-2 and transforming growth factor-β1 (TGF-β1) was analyzed by flow cytometry.Result As compared with mDC,na(i)ve T cells cocultured with imDC secreted much less IFN-γ (11.67 ± 2.18 vs.182.00±23.71,P＜0.01),IL-2 (26.67±2.96 vs.318.30± 18.62,P＜0.01),IL-4 (17.00±3.78 vs.45.33±3.48,P＜0.01),IL-10(7.00±1.00vs.158.70±10.90,P＜0.001) and IL-17 (0.66 ± 0.33 vs.238.30 ± 24.39,P＜0.001).Furthermore,imDC induced more CD4+ FoxP3+ Tregs than mDC after adding IL-2 and TGF-β1 in the coculture system for 7 days (22.70 ± 1.53 ％ vs.5.42 ± 1.27％,P＜0.01).Conclusion imDC are more effective to induce na ve T cells to Tregs,but not differentiate to TH 1/TH 2/TH 17 cells.These findings provide in vitro experimental evidence for induction of transplant tolerance by adoptive transfer of imDC.

Combination of kidney transplantation with hematopoietic stem cell infusion / 中华全科医师杂志

Ninety six female patients with chronic renal failure were randomly allocated into combination group (n =48) and control group (n =48).In combination group patients received both kidney transplantation and hematopoietic stem cell infusion,in control group patients underwent kidney transplantation only.The results showed that chronic rejection in the combination group was lower than that in the control group [2％(1/48)vs.17％ (8/48),P＜0.05)].The 1-,3-,5-and 10 y-survival rates of kidney in the combination group were 98％ (47/48),94％ (45/48),83％ (34/41) and 9/17,respectively,those in control group were 98％ (47/48),90％ (43/48),76％ (31/41) and 7/17,respectively.Infusion of donor hematopoietic stem cells can augment chimerism in early postoperative period and significantly reduce the rate of graft rejection,which is beneficial for the quality of life of the recipients.

Chimerism is required for neonatal transplantation tolerance / 中华微生物学和免疫学杂志

ObjectiveTo investigate the mechanisms of neonatal transplantation tolerance,especially the role of immature immune system and chimerism in tolerance.MethodsF1 ( or GFP-F1 ) mice were bred by crossing male C57BL/6 (or GPF transgenic C57BL/6) and female BALB/c mice. Within 24 h,newborn C57BL/6 mice were inoculated with different doses of splenocytes from F1 or GFP-F1 mice,irradiated spleen cells were used as control.Six weeks later,the mice were subjected to F1 skin grafting,and mixed-lymphocyte reaction was performed to determine their tolerance.Flow analysis was used to detect chimerism.ResultsLiving F1 spleen cells could induce chimerism and neonatal transplantation tolerance,but irradiated cells not.The chimerism in long-term tolerant mice is higher than that in chronic rejected mice,with 6.48％ ±4.02％ vs 1.57％ ±0.89％,the difference is significant in statistical analysis.The degree of neonatal transplantation tolerance is determined by the dosage of donor cells,the mice induced with 3 × 107 F1 spleen cells have 80％ long-term tolerance,but the dose of0.7×107 F1 spleen cells could only prolong allografts survival.ConclusionNeonatal transplantation tolerance is dependent on chimerism,the chimerism of donor cells leads to clonal deletion of alloreactive T cells.

Issues on Long-term Management after Liver Transplantation in Children / 대한이식학회지

With advancements of liver transplantation, the patient's survival improved remarkably. Thus the long-term survivors are increasing especially for the pediatric liver transplantation recipients. Consequently they are facing the challenge of maintaining graft function while minimizing long-term complications. In this review, I will discuss calcineurin inhibitor toxicity, problems with steroid, adherence to medical regimen, posttransplant growth, chronic graft dysfunction, tolerance.

Effects of CD28 superagonist antibody on immune inflammatory reaction early after orthotopic tracheal transplantation in rats / 第二军医大学学报

Objective: To investigate the effects of superagonistic CD28-specific monoclonal antibody JJ316 (supCD28 MAb) on in vivo proliferation of rat CD4 + CD25+ Fox P3+ Treg(T reg) cells and on allograft rejection reaction in a rat orthotopic tracheal transplantation model. Methods: Rat orthotopic tracheal transplantation models were divided into two groups in the present study. The experimental group was treated with supCD28 MAb(0.5 mg/rat) via intraperitoneal injection on the day of transplantation. Control group was injected with mIgG (0.5 mg/rat). The proportions of CD4+ CD25+ FoxP3+ T cell population in cervical lymph nodes, spleen and peripheral blood monocytes were examined by flow cytometry 5 days after operation. The tracheas were also harvested for histological evaluation. Results: The allografts of the experimental group showed greatly improved airway obliteration, infiltration of inflammatory cells, and respiratory epithelial injury compared with those of the control group. Furthermore, The experimental group had significantly increased CD4+CD25+ FoxP3+ Treg cell population in the lymph nodes, spleen and peripheral blood monocytes compared with those in the supCD28 MAb group ([5.8±1.2]% vs [16.9±4.2]%, [14.8±3.6]%, and [2.9±0.9]%, [3.3±1.3]% vs [2.8±1.4]%, respectively, P<0.05). Conclusion: SupCD28 MAb can attenuate airway inflammation injury after orthotopic tracheal transplantation.

Las células T reguladoras y su influencia en la sobrevida del trasplante renal / Regulatory T cells and their influence in kidney allograft survival

La respuesta inmune desencadenada frente a un trasplante alogénico conduce usualmente a una respuesta efectora que resulta en el rechazo del aloinjerto; sin embargo, algunos individuos mantienen un trasplante funcionante a largo plazo sin signos de rechazo (tolerancia operacional), aun en ausencia de inmunosupresión. Se ha sugerido que los mismos mecanismos son responsables para la tolerancia hacia antígenos propios y aloantígenos. Uno de estos mecanismos es la regulación inmune y se han identificado varias subpoblaciones de células con propiedades reguladoras. Entre ellas, la población celular mejor caracterizada corresponde a las células T reguladoras (Tregs). Aunque las Tregs en ratones son CD4+CD25+, en humanos el fenotipo de las Treg está restringida a las células T CD4 con alta expresión de CD25 (CD25high) y del factor de transcripción Foxp3. El análisis fenotípico y funcional de las células T reguladoras o supresoras circulantes en pacientes trasplantados tal vez sea útil para la detección de pacientes tolerantes operacionales. Además, una futura manipulación in vitro de estas células con fines terapéuticos podría conducir a lograr la inducción de tolerancia in vivo en el trasplante clínico. Aquí, revisamos la evidencia experimental y clínica del papel de las células reguladoras en la biología del trasplante.

The immune response elicited by an allogenic transplant usually leads to an effector response resulting in allograft rejection; however, some individuals maintain a long-term functioning transplant without signs of rejection (operational tolerance) even in the absence of immunosuppression. It has been suggested that the same mechanisms are responsible for tolerance to self-antigens and alloantigens. One of such mechanisms is immune regulation and several cell subsets with regulatory properties have been identified. Among them, the best characterized cell populations are the regulatory T cells (Treg). Although Treg in mice are CD4+CD25+, in humans the Treg phenotype is restricted to CD4 T cells with high expression of CD25 (CD25high) and Foxp3. Phenotypic and functional analysis of circulating regulatory or suppressor T cells in transplant patients may be useful for detection of operationally tolerant patients. Moreover, future in vitro manipulation of these cells with therapeutic purposes could lead to accomplish induction of in vivo tolerance in clinical transplantation. Herein, we review the experimental and clinical evidence for the role of regulatory cells in transplant biology.

CTLA-4Ig combined with ICAM-1 mAb promotes immune tolerance induced by donor-derived immature dendritic cells in recipient mice / 第二军医大学学报

Objective: To investigate the mechanism of CTIL-4Ig combined with Anti-ICAM-1 mAb in promoting immune tolerance induced by donor-derived immature dendritic cells (imDC) in recipient mice. Methods: Male mice were divided into 4 groups: control group (receiving only imDC), CTLA-4Ig group, ICAM-1 mAb group and CTLA-4Ig + ICAM-1 group. Mice were transfused with donor-derived imDC 7 days before they received heart transplantation in company with daily injection of ICAM-1 mAb, CTLA-4Ig or both for the following 2 weeks. Immunological analysis was performed in mice 7 days and 21 days after heart transplantation. Results: CTLA-4Ig alone or in combination with ICAM-1 mAb significantly inhibited T cells proliferation to alloantigen stimulation, impaired lymphocyte cytotoxicity, suppressed production of IL-2, IFN-γ by Th1, increased production of IL-10, and obviously decreased the production of alloantibody IgG in recipient mice treated with donor-derived imDC. ICAM-1 mAb alone had no significant effects on T cells proliferation and production of Th-derived cytokines except for IL-2. Conclusion: ICAM-1 mAb combined with CTLA-4Ig can enhance immune tolerance induced by donor-derived imDC in recipient mice through induction of T cells hypo-responsiveness, inhibition of lymphocyte cytotoxicity and B cell immunoreation, and promotion of Th2 polarization in vivo.

Prevention of Allograft Rejection by Immune Tolerance / 대한이식학회지

The development of immunosuprressants has had a significant contribution to inhibition of acute allograft rejection. However, long-term graft survival has not been realized by immunosuppressants, probably because of their nonspecific suppression of T cell activity and nonimmune side effects. The ideal way to overcome the limitations of current immunosuppressants is to induce allograft-specific immune tolerance. Transplant immunologists are exerting their efforts in achieving transplantation tolerance using three different approaches; mixed hematopoietic chimerism, costimulatory blockade, and regulation by regulatory T cells. It is expected that transplantation tolerance will soon be established as a standard immunosuppressive regimen with little side effects in preventing and reversing allograft rejection.

Clinical Strategies to Develop Transplantation Tolerance / 한양의대학술지

The development of immunosuprressants has had a significant influence on inhibition of acute allograft rejection. However, long-term graft survival has not been achieved by immunosuppressants, probably because of their nonspecific suppression of T cell activity and nonimmune side effects. The ideal way to overcome the limitations of current immunosuppressants is to induce allograft-specific immune tolerance. Transplant immunologists are exerting their efforts in achieving transplantation tolerance using four different approaches; costimulatory blockade, mixed hematopoietic chimerism, T cell depletion, and regulation by regulatory T cells. It is expected that transplantation tolerance will soon be established as a standard immunosuppressive regimen with little side effects in preventing and reversing allograft rejection.

The Effects of Maturation Resistant Donor Dendritic Cells on Alloimmune Response in Mice / 대한신장학회잡지

BACKGROUND: Although dendritic cells (DCs) are the most influential antigen presenting cells maturation of DC is the critical control point toward either activation or regulation of immunity. We hypothesized that pretreatment with donor DCs, if which were maturation-resistant in vivo, could enhance engraftment by inducing inactivated state for allo- reactive T cell clones. METHODS: Immature DCs were prepared by 6- day culture of BM cells and we used paraformaldehyde for locking the DCs as immature phenotypes. We did in vitro and in vivo MLR to evaluate the effect of maturation resistant DCs on alloreactive T cells and we confirmed the effect of DCs in MHC full mismatched skin and islet transplantation model. RESULTS: Fixed DCs in immature state were resistant to maturation stimuli and weak stimulator for allo-reactive T cells (CB6F1-->C3H). In contrast, fixed DCs in mature state stimulated allogeneic T cell proliferation effectively. Splenocytes isolated from mice 2 weeks after maturation resistant DC injection could not be reactivated and maintained naive phenotype when cocultured with allogeneic splenocytes (BALB/c-->C57BL6). Consistent with this finding maturation resistant DC treatment suppressed MLR-driven T cell division (CB6F1-->C3H) as assessed by CFSE analysis. But, CD25+ T cells depletion by treatment with anti-CD25 prior to DCs transfer attenuated this regulatory effect of DCs. In a MHC mismatched transplantation model (CB6F1-->C3H), treatment with maturation-resistant DCs 2 weeks before operation, markedly prolonged skin and islet graft survival. But C3H mice pretreated with CB6F1 DCs rejected DBA1 (H-2q) skin graft within 14 days. CONCLUSION: These findings suggest the maintenance of immaturity of DCs is a key factor in modulating alloimmune responses through dendritic cells.

Induction of skin allograft tolerance in mice by using anti-?? T cell receptor and anti-CD80 monoclonal antibodies combined with bone marrow transfusion / 北京大学学报(医学版)

Objective: To explore the role of anti-?? T cell receptor(TCR) and anti-CD80 monoclonal antibodies(mAbs) combined with donor bone marrow cells(BMCs) infusion in the induction of murine skin allografts tolerance.Methods: On day 0,2?10~8 BMCs of BALB/c mice were injected into recipient C57BL/6 mice via the tail vein,meanwhile,an intraperitoneal injection of TCR?? mAb(500 ?g) was given.On day 2,CD80 mAb was administered intraperitoneally.Skin grafting was performed on day 6.Delayed type hypersensitivity(DTH),mixed lymphocyte reaction(MLR),IL-2 reverse assay of MLR,adoptive transfer assay and chimerism detection were performed at different time points and tolerance mechanisms were investigated.Results: The mean survival time(MST) of BALB/c skin allografts in C57BL/6 recipients that were treated by anti-TCR?? and anti-CD80 mAbs combined with donor BMCs infusion was 70 days.DTH and MLR assay indicated that the tolerant mice displayed significant hyporesponsiveness.The result of IL-2 reverse test showed that clone anergy was probably involved in the formation of tolerance in the tolerant C57BL/6 mice.In vivo and in vitro adoptive transfer assay,suppressive activity in the spleens of tolerant C57BL/6 mice was observed.Chimerism existed in both the thymus and spleen of the tolerant C57BL/6 mice.The chimerism level gradually declined with time.Conclusion: Treatment of anti-TCR?? and anti-CD80 mAbs combined with donor BMCs infusion can successfully induce a long-term tolerance in BALB/c mice to C57BL/6 skin graft.Multiple mechanisms,including clone anergy,suppressor cells and chimerism are involved in the tolerance.

Cardiac transplantation tolerance induced by parabiosis in allogeneic rats / 中国免疫学杂志

Abstract Objective:To induce cardiac transplantation tolerance by parabiosis in allogeneic rats and study the mechanism of the allograft tolerance.Methods: Spleen cells 2 x 10~8 of DA and LEW rats were injected from ones to the others via the glossal vein.2 day later cyclophos-phamide(CP) 80 mg/kg was injected intraperioneally. On the third day the operation of parabiosis was carried out and then separated after 1 week.The LEW rats received DA cardiac heterotopic allografts.The survival was observed and monitored.The tolerant mechanisms were investi-gated by detection of chimerism,MLR cell-transferred tests in vivo and IL-2 reverse.Results:The cardiac allograft survival was significantly pro-longed; The detection of chimerism showed that the formation of tolerance is correlative to chimerism. MLR and cell-transferred tests in vivo demonstrated that the inhibited immune response of recipient rats is specific for donors, and suppressie cell exists in the recipient rats. The exog-enous IL-2 reverse showed that the tolerance mechanisms are relative to energy. Conclusion: The parabiosis can induce tolerance in rats and prolong rats cardiac allograft survival.The transplantation tolerance include several mechanisms.

Adenovirus-mediated gene transfer of CD40Ig gene induced long-term survival of cardiac allograft in rats / 中国免疫学杂志

Objective:To induce long-term survival of cardiac allograft in rats by adenovirus-mediated gene transfer of CEMQIg gene, and to investigate the potential mechanisms involved in the induction of transplantation tolerance. Methods: The donor cardiac allograft from DA rats was heterotopically transplanted into the abdomen of LEW recipient rats, and recombinant adenoviruses containing EGFP gene or CD40Ig gene at a dose of 5 x ICf pfu were administered via portal vein, respectively, during the operation. The graft survival was monitored by daily palpation. The expression of CD4QIg fusion protein in the recipients was detected via EIISA. The tolerant mechanism was investigated via MLR, IL-2 reverse experiment and analyzing the expression of Thl/Th2 type cytokines in the recipients.Results: Compared with the untreated recipients, the mean survival time(MST) of the cardiac allograft was not prolonged in the recipients treated with AdEGFP adenovirus, whereas MST were prolonged significantly to 142.8 ?26.8 d in the recipients administered with AdCD40Ig adenovirus. The expression of CD40Ig fusion protein remained a long time but the levels gradually decreased. The results of MLR indicated that the induced tolerance in the recipients was donor-specific. The results of IL-2 reverse experiment demonstrated that the tolerance mechanisms were involved clonal anergy at the early stage of the established tolerance. The expression pattern of Thl/Th2 type cytokines did not indicate the polarization of Thl/Th2 type cytokines in the experimental models. Conclusion: A single injection of the defined dose of adenovirus containing CD40Ig gene via portal vein during operation is enough to induce long-term survival of cardiac allograft in rats.