Critical Role for IL-6 in Hypertrophy and Fibrosis in Chronic Cardiac Allograft Rejection

Chronic cardiac allograft rejection is the major barrier to long term graft survival. There is currently no effective treatment for chronic rejection except re-transplantation. Though neointimal development, fibrosis, and progressive deterioration of graft function are hallmarks of chronic rejection, the immunologic mechanisms driving this process are poorly understood. These experiments tested a functional role for IL-6 in chronic rejection by utilizing serial echocardiography to assess the progression of chronic rejection in vascularized mouse cardiac allografts. Cardiac allografts in mice transiently depleted of CD4+ cells that develop chronic rejection were compared with those receiving anti-CD40L therapy that do not develop chronic rejection. Echocardiography revealed the development of hypertrophy in grafts undergoing chronic rejection. Histologic analysis confirmed hypertrophy that coincided with graft fibrosis and elevated intragraft expression of IL-6. To elucidate the role of IL-6 in chronic rejection, cardiac allograft recipients depleted of CD4+ cells were treated with neutralizing anti-IL-6 mAb. IL-6 neutralization ameliorated cardiomyocyte hypertrophy, graft fibrosis, and prevented deterioration of graft contractility associated with chronic rejection. These observations reveal a new paradigm in which IL-6 drives development of pathologic hypertrophy and fibrosis in chronic cardiac allograft rejection and suggest that IL-6 could be a therapeutic target to prevent this disease.     

Consideration of IL-2, IFN-γ and IL-4 expression and methylation levels in CD4+ T cells as a predictor of rejection in kidney transplant

Kidney transplantation is the certain treatment for the end-stage-kidney disease patients. However after transplantation, allograft rejection or graft dysfunction are serious problems which the patients can be encountered. In several studies new biomarkers to predict rejection episodes tried to be evaluated and cytokines are thought to be one of these biomarkers. Additionally, epigenetic regulation of the cytokine genes can be an opportunity to detect the graft survival or dysfunction that lead to rejection. In this study, we aimed to detect the expression levels and methylation profile of cytokines IL-2, IL-4 and IFN-γ to follow the clinical situation of the patients. 25 kidney transplant patients were included in our study group and peripheral blood samples were collected before and 6 months after transplantation. CD4+ T cells were separated by using magnetic separation system and expression levels are detected by qPCR while methylation profile analysis was performed by pyrosequencing. According to our study we noticed that all of the patients with allograft rejection have increased expression levels of IFN-γ. When methylation profile of the CpGs in the promotor region of IFN-γ is evaluated, +128CpG was found as methylated when compared with +122. In conclusion, epigenetic mechanisms can effect several processed in renal transplantation and further studies with higher numbers of patients are needed to detect new biomarkers for prediction of allograft rejection.     

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy--a clinicopathologic study of 96 patients.

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.     

The cytokine gene polymorphisms in patients with chronic kidney graft rejection

Chronic allograft rejection remains an important cause of morbidity after kidney transplantation. The aim of the study was to examine the association between IL-2, IL-6 and TNF-alpha promoter polymorphisms and chronic kidney allograft rejection. The study included 64 patients with long-term stable graft function and 62 with chronic allograft nephropathy. Among patients with chronic allograft nephropathy a statistically significant prevalence of the IL-6 CC genotype associated with low IL-6 expression was observed (p < 0.01, OR 3.18; 95% CI 1.27-8.15). There were no statistically significant differences in distribution of IL-2 and TNF-alpha genotypes between patients with stable graft function and chronic allograft rejection. The results of present study suggest that the genetically determined low IL-6 production may be the risk factor of chronic allograft nephropathy development.     

The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation

Recent evidence suggests that CD4+CD25+ regulatory T cells (Tregs) affect immune responses, including those to alloantigens in organ transplants. We have followed a group of liver allograft recipients with good liver graft function who have been weaned off immunosuppression (IS). The purpose of this study was to determine whether Tregs contributed functionally to the mechanisms of graft acceptance. MATERIAL AND METHODS: The functional assay used peripheral blood obtained from LTx recipients free of immunosuppression. The Whole population of CD4+ T cells and the CD4+ T cells depleted of CD4+CD25 high cells were tested for proliferation against donor versus third party stimulators. Moreover to determine the antigen-specificity of the Tregs, serially diluted numbering of CD4+CD25+ T cells were co-cultured with CD4+CD25- T cells. The proliferation responses were examined toward donor versus third party stimulators. RESULT: CD4+ T cells from all LTx recipients off immunosuppression showed hyporesponsiveness to the donor but not to third party stimulators. However, even after depletion of the CD4+CD25 high population, the cells continued to be hyporesponsive toward the donor. In four out of five cases, the suppression exhibited by CD4+CD25+ T cells was more specific for the donor. DISCUSSION: These findings suggest that donor alloantigen specific regulation by Tregs is one of multiple mechanisms that may contribute to the maintenance of liver graft survival in the absence of immunosuppression.     

Low circulating regulatory T-cell levels after acute rejection in liver transplantation.

Immune regulatory CD4+CD25+ T cells play a crucial role in inducing and maintaining allograft tolerance in experimental models of transplantation (Tx). In humans, the effect of Tx and immunosuppression on the function and homeostasis of CD4+CD25+ regulatory T cells (Tregs) is not well characterized. In this study, the frequency of Tregs in liver transplant recipients was determined based on flow cytometric analysis of CD4, CD25, CD45RO, and cytotoxic T lymphocyte antigen (CTLA)-4 markers, and the suppressor activity of Tregs was assessed in a mixed-leukocyte reaction. A link between Tregs, acute rejection, and immune-suppressive treatment was investigated. Liver transplant recipients had significantly higher Treg levels in peripheral blood pre-Tx than healthy controls. After Tx, a significant drop in the Treg fraction was observed. This reduction of circulating Tregs was transient and was associated with immunosuppression. In recipients who did not develop rejection, a relative recovery of Treg levels was seen within the first year after Tx. Recipients who experienced an episode of steroid-treated acute rejection, however, had sustained low Treg levels. The suppressive activities of CD4+CD25+ Tregs from rejectors, nonrejectors, and healthy controls on proliferation and interferon (IFN)-gamma production were indistinguishable. In conclusion, the percentage of CD4+CD25+CD45RO+CTLA-4+ quadruple-positive Tregs in peripheral blood decreases significantly after liver Tx. Treatment with methylprednisolone during Tx and for acute rejection is associated with low circulating Tregs. Despite these quantitative differences between rejectors and nonrejectors, the suppressive quality of CD4+CD25+ Tregs is identical in both groups.     

Renal allograft-infiltrating lymphocytes. A prospective analysis of in vitro growth characteristics and clinical relevance.

One-hundred consecutive human renal allograft Tru-cut needle biopsies were studied for in vitro proliferation of T lymphocytes under restrictive culture conditions containing low-dose recombinant interleukin 2. Each biopsy was entered into a blinded code and evaluated prospectively for visual evidence of growth at 24 hr and for sustained growth. Those T cell populations exhibiting sustained growth were then evaluated for cell surface phenotype by FACS; for allospecific cytotoxicity by 51Cr release; for a proliferative response to alloantigen by incorporation of [3H]-thymidine; and for secretion of IL-2, IL-4, IFN-gamma, and TNF-alpha in response to alloantigenic stimulation by ELISA. All results were compared with clinical diagnosis, immunosuppression at time of biopsy, diagnosis and phenotype by immunopathology, short-term outcome and long-term graft survival. Growth at 24 hr was predictive of acute cellular rejection (P less than 0.0005), unrelated to chronic rejection (P = 0.663) or maintenance immunosuppression (P = 0.911), and inversely correlated with cyclosporine toxicity (P = 0.051) and treatment with OKT3 (P = 0.014). The CD4/CD8 ratio of the sustained T cell populations was unrelated to that seen on histological examination (correlation coefficient = -0.098 and 0.044 for diffuse and aggregate infiltrates, respectively). Cytotoxic specificity for HLA class II was mediated by CD4+ cells and for HLA class I by CD8+ cells. Enhanced secretion of IL-2 in response to alloantigen distinguished those cells associated with irreversible allograft damage from those associated with complete functional recovery (P = 0.01). This study demonstrates that early evaluation of T cell proliferation in vitro identifies activated T cell infiltrates mediating acute cellular allograft rejection in a time frame suitable for clinical diagnostic application. It strengthens the concept that donor-specific cytotoxicity is governed by the stabilization of the alloantigen-T-cell receptor interaction by the accessory molecules CD4 and CD8, but either interaction is equally able to participate in an episode of acute rejection. Irreversible graft injury is associated with infiltrating cells that are capable of amplifying their responsiveness through secretion of IL-2.     

Function and surface phenotype of T lymphocytes infiltrating renal allografts in nonhuman primates treated with monoclonal antibodies

The phenotype and function of T lymphocyte cell lines established in vitro from kidney biopsies at the time of acute cellular rejection were studied using a nonhuman primate renal allograft model. Our objectives were to investigate the function and surface phenotype of cells that infiltrate renal allografts in animals that were untreated, that were given subtherapeutic cyclosporin, or that developed rejection after treatment with monoclonal antibodies to IL-2R B chain (CD25), immune cell adhesion molecule-1 (ICAM-1), or CD8. Lines from allograft biopsies and peripheral blood were expanded in vitro using solely human recombinant IL-2 and analyzed after 6-20 days in culture. We found that the large majority of cells cultured from cynomolgus allografts at the time of acute rejection or, when possible, assayed directly without culture, were CD3+4-8+ T lymphoblasts that possessed donor-specific cytolytic function and an NK-line, cytotoxic activity. In contrast, it was rarely possible to establish T cell lines exhibiting donor-specific cytotoxic activity from the blood except in the absence of immunosuppression or during CsA taper. A stable number of graft-derived CD4+8- cells was only observed in an unsuppressed animal 2 days after transplantation in the absence of manifest signs of rejection. Taken together, the above data indicate that similar T lymphocyte populations associated with allograft rejection are present in acutely rejecting allografts after the various types of immunosuppressive therapy. Since the infiltrating cells were similar to those obtained prior to therapy, recurrent rejection most likely represents cells that have escaped elimination. The T cells derived from monkey grafts differ from those from human renal allografts by the decreased frequency of CD4+ cells. Whether this difference is species-related or therapy-related is not known.     

Correlation of in vitro CD4+ T helper cell function with clinical graft status in immunosuppressed kidney transplant recipients.

We recently identified three distinct T helper pathways which contribute to interleukin-2 (IL-2) production by human peripheral blood lymphocytes following stimulation with HLA alloantigens. In two of these pathways, CD4+ T helper cells respond to alloantigen using either self antigen-presenting cells (sAPC)* or allogeneic antigen-presenting cells (aAPC). A third pathway involves CD8+ T helper cells using aAPC. Previous in vitro studies have shown that the T helper pathway dependent on CD4+ T helper cells and sAPC (CD4-sAPC) is the most susceptible to suppression by cyclosporine. In the present study, we measured alloantigen-stimulated IL-2 production by PBL from 42 kidney transplant recipients to characterize the strength of the three T helper-APC pathways. In 58% of patients, a loss of the CD4-sAPC pathway was identified and was correlated with cyclosporine treatment. However, several patients not receiving cyclosporine also exhibited a similar loss of T helper cell function, suggesting that cyclosporine is not the only factor involved. Of 27 patients exhibiting depressed CD4-sAPC function, none had evidence of ongoing/recent graft rejection. In contrast, of 11 patients with no defects in the three pathways of in vitro T helper cell function, 6 had evidence of chronic graft rejection. Of considerable interest are the data obtained from a separate group of 4 patients who had episodes of acute rejection during the study. In each case, at the time of the rejection episode, all exhibited an intact CD4-sAPC pathway. However, samples tested prior to the rejection episode or after successful treatment of the rejection episode showed a depressed CD4-sAPC pathway. These results suggest that depression of the CD4-sAPC pathway represents adequate immunosuppression for graft retention and that patients not exhibiting such suppression are at increased risk for both acute and chronic graft rejection. These data may have relevance for diagnosis and/or prediction of graft rejection and may provide an in vitro method of monitoring the functional degree of immunosuppression in transplant recipients.     

Macrophage polarization in kidney transplant patients

BackgroundMacrophages can oscillate between two functionally distinct states: proinflammatory M1 and anti-inflammatory M2. Classically- activated M1 macrophages produce proinflammatory cytokines (TNF-α, IFN-ƴ, and IL-6), which ares associated with graft dysfunction/rejections. In contrast, alternatively-activated macrophages M2 produce anti-inflammatory cytokines (IL-10) that are involved in host defense, tissue repair/remodeling, debris scavenging, and immune regulation, thereby helps to improve long-term graft survival.MethodsIn this study, we have identified graft dysfunction or rejection by biopsies using immunohistochemistry. Flow cytometry was used to detect M1 (CD163+, CD206+, and CD200R+) and M2 (CD86+, CD80+, and CD68+) macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to measure a panel of cytokines.ResultsHistological analysis of the kidney transplants (n = 30) was used to distinguish those with acute/chronic allograft rejection (n = 15) from those with stable kidney function (n = 15). Flow cytometry results showed that patients with graft rejection exhibited macrophages with decreased expression (33.28%) of M2 macrophage markers (CD163+, CD206+, and CD200R+) and reduced production of IL-10 (as detected using ELISA). However, 71.33% of the macrophages were found to have M1 markers (CD86+, CD80+, and CD68+; p = 0.002) and produced proinflammatory cytokines (TNF-α, IFN-ƴ, and IL-6) by ELISA (p = 0.001) when compared with the healthy control group. In contrast, stable kidney transplants had 65.58% M2 and 27.66% M1 macrophages (p = 0.03) and produced IL-10. These findings suggest that M1 macrophages dominate in kidney grafts with dysfunction or rejection, whereas M2 macrophages dominate in kidney grafts with stable function.ConclusionOur observations implicate a major shift towards M2 macrophages in stable kidney transplants, which are markedly downregulated in patients with graft dysfunction or rejection. In contrast, an increased frequency of M1 macrophages remained dominant in the pathophysiology of kidney transplants undergoing active dysfunction or rejection.     

Prevalence and immunohistochemical findings of subclinical kidney allograft rejection and its association with graft outcome

Subclinical acute rejection (SAR) occurs in about 30% of stable renal transplant patients and may be a risk factor for a poor allograft outcome. In the present study, the prevalence and clinical features of subclinical rejection, and the expression of immune activation markers in surveillance graft biopsies were assessed and correlated with late graft outcomes. Protocol biopsies were obtained at 2 and 12 months post-transplant in 32 and 26 patients, respectively, with stable renal function. The Banff 1997 criteria were used for histological diagnosis. Graft function and survival and proteinuria were assessed during the 36 months of follow-up. Immunohistochemical evaluation of cell subpopulations and immunoactivation markers were performed on protocol biopsies. The prevalence of SAR at 2 months and of chronic allograft nephropathy (CAN) at 12 months in representative biopsies was 55 and 50%, respectively. Patients with SAR presented mononuclear cell infiltration with an increased expression of CD3, CD4, CD68, IL-2R and granzyme B. Kidney graft function was significantly worse in patients with SAR at 2 months who had chronic rejection on biopsy at 12 months, but SAR was not associated with a worse graft function, greater proteinuria or a lower graft survival in 3 yr of follow-up. In conclusion, we found an elevated prevalence of SAR at 2 months after transplantation with an increased expression of activation markers. Although an association of SAR with poor graft outcome was not observed, our results suggest that SAR is an immunologically active process and underscore the importance of protocol biopsies in the surveillance of transplanted kidneys.     

CD40 expression on graft infiltrates and parenchymal CD154 (CD40L) induction in human chronic renal allograft rejection

BACKGROUND: CD40-CD154 (CD40L) costimulatory signaling plays a pivotal role in the effector mechanisms of transplant graft rejection. In animal models, CD40-CD154 blockade induces long-term graft acceptance concurrent with an absence of chronic rejection (CR) lesions. Given the critical importance of CD40-CD154 interactions in the development of chronic transplant allograft rejection, the relevance of in situ CD40 and CD154 expression was assessed in human chronic renal allograft rejection. METHODS: The expression of CD40, CD154, CD68, and T-cell receptor (TCR)alpha/beta was analyzed by immunohistochemistry. Serial cryostat sections of snap-frozen core renal allograft biopsies were obtained from 30 renal transplant patients. Biopsy specimens received diagnoses of CR (N = 23) according to the Banff classification and were compared with controls (N = 7) consisting of stable allografts and normal kidney tissue. RESULTS: Striking CD40 staining of graft cellular infiltrates (P = 0.016) was observed in renal allografts with CR compared with controls. The CD40+ cellular infiltrates in CR were predominantly TCR alpha/beta + T cells and some CD68+ macrophages. These findings were contrasted by the low-level CD40 expression detected in glomeruli and tubules of CR and controls. However, glomerular induction of CD154 was observed in CR allografts (P = 0.028) as compared with controls. CD154 immunoreactivity was demonstrated on glomerular endothelial, epithelial, and mesangial cells. Moderate CD154 expression was detected on tubular epithelial cells, and only weak CD154 immunoreactivity was observed on the infiltrates in isolated CR cases. CONCLUSION: In human chronic renal allograft rejection, CD40 is expressed on graft-infiltrating cells of the T cell and macrophage compartments. CD154 expression is induced on glomerular and tubular epithelial cells during CR, demonstrating another novel source of CD154 expression. The data substantiate the potential contributory role of an interaction between CD40+ graft-destructive effector T cells and macrophages with CD154+ renal allograft parenchymal cells in the development of chronic renal allograft rejection.     

CD28 superagonist antibody treatment attenuated obliterative bronchiolitis in rat allo-orthotopic tracheal transplantation by preferentially expanding Foxp3-expressing regulatory T cells

Obliterative airway disease (OAD) due to chronic alloantigen rejection remains a major challenge for long-term graft survival in lung transplantation. It is known that superagonistic CD28-specific monoclonal antibody JJ316 (supCD28 MAb) has the ability to induce regulatory T cells (Tregs) efficiently. Here we used a rat orthotopic tracheal transplantation model to investigate the effects of supCD28 MAb on expanding Tregs in vivo and its application in suppression of acute and chronic airway allograft rejection. SupCD28 MAb administration revealed a significant increase in the CD4+CD25+ T cells, CD4+FoxP3+ T cells, and CD4+CD25+ FoxP3+ T cells population among CD4+ T cells in spleen, peripheral blood, as well as cervical lymph nodes. The allografts from animals treated with supCD28 MAb showed significantly less airway obliteration and rejection of the respiratory epithelium compared with allografts of the mouse immunoglobulin G-treated group on the 5th day and the 60th day after transplantation. Overall, our data demonstrated that an intraperitoneally administrated low dose of supCD28 MAb was sufficient to induce Treg cell expansion in vivo and was effective in protecting the airway graft from early rejection and chronic OAD development. These findings provide the basis for new therapies to prevent OAD and perhaps rejection of allografts in other human transplantations.     

C4d-positive chronic rejection: a frequent entity with a poor outcome

BACKGROUND: Chronic rejection (CR) is an important cause of kidney graft loss. Some studies have suggested the role of antibodies mediating chronic graft dysfunction. In this context, C4d identification is an important tool to evaluate antibody-mediated rejection. METHOD: This is a retrospective study that analyzed 80 patients with histological diagnosis of chronic allograft nephropathy (CAN) according Banff 97 and no evidence of transplant glomerulopathy. These patients had renal biopsies available for C4d immunoperoxidase staining at the time of diagnosis. Cases were reclassified by the presence of C4d in peritubular capillaries. RESULTS: C4d was negative in 30 cases (37.5%) and positive in 50 (62.5%). C4d+ group had more female and highly sensitized patients (PRA) at transplant. All variables were similar between C4d- and C4d+ cases at diagnosis time, but more C4d+ patients presented proteinuria (>0.3 g/L). Patients were submitted to various immunosuppression regimens after the CAN diagnosis. Four years after the diagnosis, death-censored graft survival was 87% for C4d- and 50% for C4d+ (P=0.002). In the multivariate Cox regression analysis, C4d+, PRA>10%, and vascular intimal proliferation were the variables that present higher relative risk for graft loss. CONCLUSION: These data indicate that C4d positive chronic rejection is very common, associated with proteinuria, and has a poor outcome. A larger study is warranted to identify which immunosuppressive regimen may modify the poor course of this entity.     

Reduced CD4+ CD25++ CD45RA− Foxp3hi activated regulatory T cells and its association with acute rejection in patients with kidney transplantation

BackgroundIt was found that regulatory T cells (Tregs) importantly affect the maintenance of the kidney graft. However, Tregs are a heterogeneous population with less to more suppressive activity. The aim of this study was to determine the effects of different subsets of Tregs, as well as their ratio to effector T cells (Teff), on kidney transplantation outcomes.MethodsA total of 58 participants were enrolled in this study and divided into four groups: (i) first kidney transplant recipients (stable 1); (ii) second kidney transplant recipients (stable 2); (iii) transplant recipients with acute rejection (AR); and (iv) healthy control subjects. By using flow cytometer, the frequencies of CD4⁺ CD25⁺⁺ CD45RA⁻ Foxp3^hi activated Tregs (aTregs), CD4⁺ CD25⁺ CD45RA⁺ Foxp3^lo resting Tregs (rTregs), CD4⁺ CD25⁺ CD45RA⁻ Foxp3^lo non-suppressive T cells, CD4⁺ CD25⁺ Foxp3⁻ cells Teff, and total Tregs were analyzed in all subjects.ResultsThe frequency of aTregs (as well as the ratio of aTregs/Tregs) was significantly lower in the AR patients than the other three groups. In contrast to AR patients, stables 1 and 2 had a higher aTreg/Treg ratio than those in the control group. Although patients with AR had a significantly lower total Tregs than the other three groups, the balance of total Tregs and Teff was similar between patients with and without AR.ConclusionPatients with AR had poorer immunoregulatory properties than those with normal graft functioning, as well as those in the control group. These reduced immunoregulatory properties in patients with AR could lead to graft rejection.     

T-cell alloimmunity and chronic allograft dysfunction

Solid organ transplantation is the standard treatment to improve both the quality of life and survival in patients with various end-stage organ diseases. The primary barrier against successful transplantation is recipient alloimmunity and the need to be maintained on immunosuppressive therapies with associated side effects. Despite such treatments in renal transplantation, after death with a functioning graft, chronic allograft dysfunction (CAD) is the most common cause of late allograft loss. Recipient recognition of donor histocompatibility antigens, via direct, indirect, and semidirect pathways, is critically dependent on the antigen-presenting cell (APC) and elicits effector responses dominated by recipient T cells. In allograft rejection, the engagement of recipient and donor cells results in recruitment of T-helper (Th) cells of the Th1 and Th17 lineage to the graft. In cases in which the alloresponse is dominated by regulatory T cells (Tregs), rejection can be prevented and the allograft tolerated with minimum or no immunosuppression. Here, we review the pathways of allorecognition that underlie CAD and the T-cell effector phenotypes elicited as part of the alloresponse. Future therapies including depletion of donor-reactive lymphocytes, costimulation blockade, negative vaccination using dendritic cell subtypes, and Treg therapy are inferred from an understanding of these mechanisms of allograft rejection.     

Triple immunosuppression with or without basiliximab in pediatric renal transplantation: acute rejection rates at one year

Acute rejection (AR) is a major determinant of chronic allograft dysfunction and graft survival. This study evaluated the effect of basiliximab on AR in pediatric renal transplantation on triple immunosuppression. Forty-three transplantations (25 males and 18 females; mean age 14.9 +/- 3.6 years) were performed between 1996 and 2002. Thirteen of the grafts came from cadaveric donors and 30 from living-related donors. All patients were placed on immunosuppression with prednisolone + (azathioprine or mycophenolate mofetil) + (cyclosporine [CYA] or tacrolimus). Basiliximab was also administered in 20 cases. The respective rates of biopsy-proven AR in the basiliximab group (BG) and the standard-regimen group (N-BG) were 0% vs 17.4% (P >.05) at 1 month posttransplantation; 0% vs 26.1% (P <.05) at 3 months; 0% vs 26.1% (P <.05) at 6 months, and 7.1% vs 26.1% (P >.05) at 12 months. In the N-BG group the 1- and 3-year graft survival rates were 91.3% (21/23) and 83.3% (15/18), respectively. The mean glomerular filtration rate (GFR) in the first year after the transplantation was 75 +/- 33 mL/min/1.73 m(2) in the N-BG and 98 +/- 21 mL/min/1.73 m(2) in the BG patients (P <.05).Basiliximab significantly reduced the rates of acute rejection at 3 and 6 months after pediatric renal transplantation. The GFR in the first year was significantly higher among the patients treated with basiliximab, which was well tolerated by all patients and caused no significant adverse effects. The effect of basiliximab on long-term graft survival and chronic allograft dysfunction deserves further investigation.     

Acute lung transplant rejection is associated with localized increase in T-cell IFNgamma and TNFalpha proinflammatory cytokines in the airways

BACKGROUND: Allograft rejection remains a major cause of morbidity and mortality after lung transplantation and is associated with increased gene expression for proinflammatory cytokines. T cells are a major cell type involved in graft rejection. There have been no previous studies of cytokine production by T cells from blood, bronchoalveolar lavage (BAL), and intraepithelial T cells from bronchial brushings (BB) during rejection episodes; we hypothesized that T-cell proinflammatory cytokines would be increased in the airways during rejection episodes despite standard immunosuppression regimens. METHOD: To investigate changes in cytokine profiles during rejection episodes, whole blood, BAL, and BB from stable lung transplant patients and those with acute rejection were stimulated in vitro and intracellular cytokine production by CD8- (CD4+) and CD8+ T-cell subsets determined using multiparameter flow cytometry. RESULTS: Transforming growth factor (TGF)-beta was significantly decreased in blood CD4+ and CD8+ T cells while interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha were significantly increased in BAL CD4+ and CD8+ T cells in patients with evidence of rejection. There was no change in CD4:CD8, interleukin (IL)-2, or IL-4 between stable and rejecting groups. CONCLUSIONS: Acute lung transplant rejection is associated with decreased intracellular T-cell TGFbeta in blood and increased intracellular IFNgamma and TNFalpha in BAL CD4+ and CD8+ T cells. Drugs that effectively reduce airway T-cell IFNgamma and TNFalpha proinflammatory cytokine production may improve current protocols for reducing acute graft rejection in lung transplant patients.