The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching.

BACKGROUND: Induction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS). OBJECTIVE: This study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching. METHODS: We retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT. RESULTS: The rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure. CONCLUSION: We conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.

Current state of clinical trials regarding liver transplant rejection.

BACKGROUND: Liver transplant (LT) is the second most common transplant intervention. The rate of acute cellular rejection (ACR) is 15-25% after LT, while being higher in chronic rejection (CR). Clinical trials had a major role in getting more potent and selective immunosuppressive medications. Our study plays an important role by evaluating and tracking clinical trials related to liver transplant rejection, focusing on interventional therapeutic trials. METHODS: On October 28, we searched Clinicaltrials.gov for interventional clinical trials related to liver transplant rejection. A total of 27 clinical trials included in this study. Characteristics on each trial were collected, and availability of linked publications was searched using Medline/PubMed and Embase/Scopus. Content of publications was reviewed and main findings were summarized. RESULTS: Majority of trials were completed (15 out of 27). Eleven trials had between 11 and 50 participants, and 10 had above 100. The study duration was between 1 and 4 years for the majority of trials (16 trials), with an average of 3.77 years. Most of the trials were done in Europe/UK/Russia (n = 12). The results were provided in 9 trials but published in 4, showing the possible tolerogenic efficacy of MSC in liver transplantation, increased success of immunosuppression (IS) withdrawal after sirolimus addition, efficacy of Alemtuzumab, normal graft function and stability within 1 year of immunosuppression withdrawal. CONCLUSION: This study revealed a low number of trials, lack of variety in location and low publishing rates. The focus of trials was mainly towards side effects and safety of immunosuppressants, and their withdrawal. These trials reached results that must be built on to reach definitive guidelines and treatment strategies. This highlights the need for better management of human and financial resources, in order to reach new and more effective therapeutic strategies, leading to the decrease in rate of LTR.

Effect of donor-to-recipient HLA matching in low-immunological risk kidney transplant recipients without induction therapy on acute rejection, graft survival, infections, and surgical complications at 3 years: The road towards new recommendations.

BACKGROUND: Donor-to-recipient human leukocyte antigen mismatching is considered one of the strongest determinants for graft and patient survival in kidney transplant recipients (KTR). OBJECTIVE: This retrospective study discusses the impact of HLA matching as low immunological risk KTR without induction therapy. MATERIAL AND METHODS: Records of 80 adult kidney transplant patients were reviewed with three years of the follow-up. All patients had panel reactive antibodies (PRA) < 20%, absence of donor-specific antibodies (DSA) and did not receive the induction therapy. These patients were divided into two groups according to their HLA matching between donor and recipient: 55 patients with ≥ 3 HLA matches (Group I; low immunogenicity) were compared to 25 patients with <3 HLA matches (Group II; high immunogenicity). The primary endpoints included the rate and severity of acute rejection (AR) episodes, graft function (creatinine level), and survival at 1, 3, 6, 12, and 36 months. Secondary endpoints include the rate and type of infections at one-year, surgical complications at one-year, and patient survival at 1, 6, 12, and 36 months after kidney transplantation. Baseline demographic characteristics were comparable between the two groups except for recipient age, donor gender, and pre-transplant dialysis time. RESULTS: There was no significant difference observed between two groups at one-year in infection rate, the length of hospital stay, AR severity, the rate of cytomegalovirus infection, and the occurrence of delayed graft function. However, the rate of AR, the graft function upon discharge, and the rate and type of surgical complications at one-year were significantly higher in Group II (high immunogenicity). The patient and graft survival at three years, the death-censored graft survival, and the serum creatinine levels at 1, 3, 6, 12, and 36 months were similar between two groups. Two deaths occurred in each group (NS). CONCLUSION: In our center, the donor-to-recipient HLA mismatch is not considered an immunological risk factor in low-risk kidney transplant recipients (PRA < 20% and absence of DSA).

Cytomegalovirus infection in kidney transplant patients: Prevalence, risk factors, and impact on outcome - A local multicentre experience.

BACKGROUND: CMV infection prevalence in kidney transplant recipients (KTR) is reported to be high in the literature, reaching rates of over 80%. OBJECTIVES: The primary endpoints were the evaluation of the prevalence, the risks factors, and the effects of CMV infection on graft function and survival, as well as patient survival at three years after kidney transplantation. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 288 kidney transplant patients operated in three Lebanese transplant centers between 1998 and 2017 with three years of follow-up. The patients were divided into two groups: those free of any CMV infection (271 patients (94%); Group I) and those who suffered from CMV infection (17 patients (6%); Group II). RESULTS: Baseline demographics of the two groups were similar, including recipient and donor gender and age, cause of renal disease, recipient body mass index, pre-transplant fasting blood sugar and dialysis duration, HLA matching between donor and recipient, degree of sensitization in the recipient, type of CMV prophylaxis, maintenance immunosuppression and immunological characteristics. The prevalence of CMV infection is 5.9% among KTR. There were significant differences between the two groups concerning the type of induction therapy and the duration of anti-CMV prophylaxis. The rate of infected patients and infectious episodes were significantly higher in Group II. At 3-years, graft function and survival, patient survival, and the rate of new-onset diabetes were similar between the two groups. CONCLUSION: The present study is the first to explore the incidence and risk factors of CMV in kidney transplant patients in Lebanon. Comprehensive nationwide studies are therefore necessary to determine the epidemiology and risk factors of CMV infection after kidney transplantation in Lebanon.

The impact of gender matching between donor and recipient on the outcome of kidney transplant patients: A retrospective study.

The influence of donor and recipient gender on patients postkidney transplant (KT) is still controversial, and literature data do not present unanimous conclusions. We were concerned with the gender impact on the outcome of kidney transplantation at the level of acute rejection (AR), graft function represented by serum creatinine level, delayed graft function (DGF), graft survival, and infection rate. The impact of gender matching between donors and recipients was studied in 299 KT recipients performed in the Transplantation Unit, Middle East Institute of Health, Bsalim, Lebanon, between November 1998 and September 2014. The patients were divided into the following groups: Group I (131 patients, male donor to male recipient), Group II (55 patients, male donor to female recipient), Group III (88 patients, female donor to male recipient), and Group IV (25 patients, female donor to female recipient). AR and DGF were not statistically different among the four groups. Moreover, all groups showed excellent graft survival with no statistical difference. Interestingly, human leukocyte antigen AB-DR matching (P < 0.001) and sensitization were statistically different among the four groups (P = 0.05). The number of patients with infections was statistically significantly lower in Group I (35.4%) and Group III (37.5%) (P = 0.35). Most importantly, graft function, represented by serum creatinine, showed a statistically significant difference among the four groups (P <0.004), with Group II (male to female) and Group IV (female to female) showing the best improvement in five-year survival. However, Group III (female to male) had the worst posttransplant graft function. These results revealed that gender impacts graft function, and Group II, male donor to female recipient, had the best 5-year graft function. This emphasizes that gender should be regarded as a determinant for the success of kidney transplantation.

Sex matching plays a role in outcome of kidney transplant.

OBJECTIVES: The effect of sex matching between donors and recipients was studied in 135 kidney transplant operations performed in our center between December 1998 and December 2007. MATERIALS AND METHODS: Patients were divided into 4 groups: group 1 (63 patients, male donor-male recipient), group 2 (25 patients, male donor-female recipient), group 3 (37 patients, female donor-male recipient), and group 4 (10 patients, female donor-female recipient). Except for donor age, recipient body mass index and donor-recipient HLA AB-DR matching, recipient, and donor demographics, and the immunosuppression were comparable in all groups. RESULTS: Acute rejection and the need for antithymocyte globulin Fresenius rescue therapy were comparable between the 4 donor-recipient combinations. Excellent 1-year actuarial patient and graft survival, comparable hospital stay, and incidence of delayed graft and slow graft function were comparable between the 4 groups. One death occurred, each, in groups 1 and 2; posttransplant complications being comparable. While 1-year graft survival (death censored and uncensored) were comparable, 1-year graft function (serum creatinine) showed that the worst graft function was seen in group 3 (female-to-male). Significant differences between the 4 patient groups also were seen in pretransplant and posttransplant hemoglobin levels as well as in posttransplant arterial hypertension and high-density lipoprotein cholesterol blood levels. Other metabolic indices were generally comparable between the 4 patient groups. CONCLUSIONS: These results revealed that sex mismatching (group 2, male donor to female recipient) had the best 1-year graft function but the same 1-year patient and graft survival.

Infectious complications in kidney transplant: a Lebanese perspective.

OBJECTIVES: Infections remain a frequent, potentially life-threatening complication of kidney transplant. SUBJECTS AND METHODS: Between 1998 and 2006, we evaluated the incidence of infections in 114 kidney transplant patients, with a 1-year follow-up. All patients received a posttransplant anti-infectious prophylaxis regimen. Induction therapy was given to 94 patients (82.4%), and maintenance immunosuppression consisted of calcineurin inhibitor (cyclosporin microemulsion or tacrolimus), together with mycophenolate mofetil and prednisone. RESULTS: In total, 56 patients (49.1%) developed a total of 95 infections up to 1-year after kidney transplant, including 46 in-hospital infections in 38 patients. Bacterial infections were the most frequent (97.8%), and were mainly urinary, followed by drain, central line catheter, and pulmonary infections. The most-frequent isolated bacteria were E. coli, followed by Klebsiella, Acinetobacter, and Pseudomonas. No viral infections were detected. Up to 1 year after discharge from the hospital, 49 infections occurred in 26 patients, of which 79.5% were bacterial; mainly urinary tract infections due to E. coli, in addition to 7 cases of cytomegalovirus, 1 herpes, and 2 cases of fungal infections. CONCLUSIONS: This is the first Lebanese study that deals with posttransplant infections in kidney transplant patients and underscores the importance of close patient monitoring and follow-up. Comparison with international data shows similar patterns.

Kidney transplantation in a patient with aortic bi-iliac endovascular graft: case report and literature review.

Arterial hypertension is a leading cause of both vascular diseases and chronic renal failure. With the increasing incidence of patients suffering from hypertensive vascular disease, namely aorto-iliac atherosclerosis and aneurysms, more candidates are referred for kidney transplantation (KT). Staged or simultaneous surgical repair of aorto-iliac lesions with KT have long been described and studied. In this report, we discuss the case of a patient with infrarenal abdominal aortic aneurysm, having an endovascular bifurcated aortic bi-iliac stent (EVBAIS) introduced, who underwent a KT 3 months after his vascular surgery without any postoperative complication. This case, as well as other previous studies, supports the fact that the presence of an EVBAIS does not contraindicate KT.

Effect of recipient age on the outcome of kidney transplantation.

We investigated the effect of recipient age (RA) on kidney transplantation outcome in 107 transplant patients, with a follow-up of 1 year. Patients were divided in 3 groups: Group A (RA<50 years; 72 patients), Group B (RA 50-60 years, 19 patients), and Group C (RA>60 years; 16 patients). The rate and severity of acute rejection, infection rate and type, delayed graft function, hospital stay, creatinine levels (3, 6, 12 months), incidence at 1 year of post-transplant hypertension, cholesterol and triglycerides blood levels, and the rate of post-transplant surgical complications, and 1-year graft and patient survival were comparable between the 3 groups. However, creatinine blood level at 1 month and the 1-year fasting blood sugar were significantly higher in Group B. The RA does not seem to be of a significant predictive value, good selection and pre-transplant patient workout are important factors for a better outcome.

Effect of pretransplant hemoglobin blood level on kidney transplant outcome.

OBJECTIVES: We investigated the effect of pretransplant hemoglobin level on the outcome of kidney transplant. PATIENTS AND METHODS: Patients were divided in 2 groups: group A < 10 g/dL (80 patients; PTHb < 10 g/dL), and group B > 10 g/dL (69 patients; PTHb = 10 g/dL), and were matched regarding donor age, recipient sex, blood group, donor recipient HLA, and Cytomegalovirus status. RESULTS: The frequency of acute rejection, together with the timing of rejection, the need for antithymocyte globulin Fresenius rescue therapy, infection rate, and posttransplant surgical complications were comparable between both groups. While the 1-year actuarial patient and graft survival rates, delayed graft function, and slow graft function rates were comparable between both groups, longer hospital stay was required for group B (> 10 g/dL) patients (P = .005). Mean serum creatinine levels upon discharge (P = .02), at 6 months (P = .05), and 1 year (P = .02) after discharge were higher in group B (> 10 g/dL) patients. While posttransplant hemoglobin levels were lower than pretransplant levels, they were higher in group B (> 10 g/dL) compared with group A (< 10 g/dL), (P = .019). CONCLUSIONS: Pretransplant hemoglobin level does not affect the outcome of kidney transplant, except for creatinine levels at 1 year.

Malignant fibrous histiocytoma: a case report and literature review.

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in late adult life. It occurs most frequently in the extremities (70%), followed by the retroperitoneum (16%). The occurrence of MFH in the spermatic cord is extremely rare (approximately 50 cases in the literature). We are reporting one case of MFH of the spermatic cord that presented as a hard painful inguinal mass. The patient was treated by a right radical orchiectomy followed by postoperative radiotherapy. The patient remained alive, with no local recurrence after 30 months of follow-up.

Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation.

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.

HLA class II allele frequencies in the Lebanese population.

Human leukocyte antigens (HLA) allele determination is becoming an increasingly important aspect in the field of transplantation as well as in the area of HLA association with a number of diseases. Through Lebanon's history, this country, situated at a crossroads between Europe, Asia and Africa, has been a host for various populations of different ethnicities. The aim of our study is to determine whether allele polymorphisms in the Lebanese population present a distinguishing feature. Although data on HLA phenotypic polymorphisms in Lebanon have been reported in the literature, our study is the first to examine frequencies of HLA polymorphisms in the country at the molecular level. Allele frequencies of the Lebanese population were analyzed and compared with those of other populations. HLA class II genotyping of DRB1* and DQB1* loci by PCR-sequence-specific primer (SSP) was performed on 191 unrelated Lebanese subjects of both sexes and of different regions and sects in Lebanon. The study revealed that DRB1*1101, DRB1*0401 and DRB1*0301 were the three most common DRB1* alleles observed (respective allele frequencies of 0.302, 0.164 and 0.096). In the DQB locus allele group, DQB1*0301 (allele frequency of 0.384) was highly predominant followed by the DQB1* 0501, DQB1*0201 and DQB1*0302 with respective allele frequencies of 0.199, 0.195 and 0.103. These results confirm previous serological studies and show the high prevalence of DRB1*1101 and DQB1*0301 in Lebanon, which could be explained by the high frequency of consanguineous marriages in the population. The presence of other common alleles is consistent with historical data showing that the Lebanese population is an admixture of various ethnicities.

Comparison of daclizumab, an interleukin 2 receptor antibody, to anti-thymocyte globulin-Fresenius induction therapy in kidney transplantation.

The efficacy and safety of daclizumab and anti-thymocyte globulin-Fresenius (ATG-F) as induction therapy in kidney transplantation (KT) were investigated in 45 KT performed in our center between March and May 2002. Group II (n=10) received daclizumab as induction therapy, and Group I (n=35) were induced with a single intraoperative bolus therapy of ATG-F. All patients were at low-risk, and the recipient and donor demographics, as well the immunosuppression regimen employed were comparable in both groups. Drug safety, assessed by the occurrence of side effects, was almost comparable in the two groups, except for more thrombocytopenia in Group II (P<0.0004). Acute rejection (AR) occurred in 10% in Group I and 11.4% in Group II (P=NS). There were more infections in Group II (42.8%) than in Group I (10%) (P<0.009). Bacterial and viral infections were more common in Group II (69 and 23%) than in Group I (10 and 0%) (P<0.05). The hospital stay was similar in both groups. Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.23+/-0.11, 1.21+/-0.06, 1.25+/-0.11 and 1.35+/-0.08 in Group I and 2.18+/-0.43, 1.49+/-0.16, 1.49+/-0.16 and 1.35+/-0.08 in Group II, respectively. While better serum creatinine levels were observed in Group I upon discharge (P<0.048), this was due to the presence of more sensitized patients in Group II. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%, respectively). Although both daclizumab and ATG-F were effective and safe as induction therapy in KT, less bacterial and viral infections and lower early serum creatinine levels were noted in daclizumab-treated patients.

Intraoperative anti-thymocyte globulin-Fresenius (ATG-F) administration as induction immunosuppressive therapy in kidney transplantation.

We reviewed 43 adult kidney transplant patients (32 males and 11 females, 14-68 years of age) performed at our center between July 1999 and February 2002. Donors (39 males and 4 females) comprised two cadaverics, five living-related and 36 living-unrelated; age 18-44 years. Indications for kidney transplantation (KT) were: chronic glomerulonephritis (8), re-transplantation (4) and chronic pyelonephritis (3); kidney disease was unknown in 15 cases. ATG-F was given as a single intra-operative bolus induction therapy in 26 patients; extended ATG-F dose was given in 17 patients because of a high sensitization status, slow graft function (SGF) or development of calcineurin inhibitors toxicity. ATG-F was stopped in seven out of 17 patients because of thrombocytopenia or severe anemia. ATG-F-related fever occurred in six patients. Acute rejection (AR) occurred in eight patients (18%) 5-11 days post-KT. ATG-F was given in three steroid-resistant AR. Infection occurred in 19 patients (44%) for a total of 32 infectious episodes comprising 24 bacterial infections (nine urinary, seven catheter-related and three respiratory), six viral infections (five CMV and one herpes) and two fungal infections (one pulmonary aspergillosis and one catheter-related candidiasis). The hospital stay was 8-75 days for a median of 13 days. The mean serum creatinine upon discharge, at 1 and 6 months after KT were: 2.04+/-0.37, 1.43+/-0.16 and 1.29+/-0.08, respectively. One patient lost his graft on day 9 because of graft microthrombi related to Factor V-Leiden mutation. The 6 months actuarial patient and graft survival were 100 and 97.6%, respectively. ATG-F as a bolus therapy is an effective and safe induction treatment in KT.

Tacrolimus (FK506) versus cyclosporin A microemulsion (Neoral) maintenance immunosuppression: effects on graft survival and function, infection, and metabolic profile following kidney transplantation (KT).

We reviewed two groups of kidney transplant patients receiving neoral (Group I, 27 patients) or FK506 (Group II, 25 patients) as maintenance immunosuppression between December 1998 and May 2002. The recipient and donor demographics and induction therapy were comparable in both groups except for more highly sensitized patients in Group II. Acute rejection (AR) rate and timing were similar in both groups except for more steroid resistant AR in Group II (P=0.04). Infections rate was similar in both groups (25.9% in Group I and 36% in Group II; P=N.S.), but there were less viral infections in Group I (0%) than Group II (29%; 4 CMV). CMV infections were related to the presence in Group II of more CMV-negative recipients getting kidneys from CMV-positive donors. The metabolic profile was comparable between the two groups, except for a better HDL in Group II (48.2+/-7.6) versus Group I (45+/-2.2; P=0.021). Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.62+/-0.32, 1.4+/-0.17, 1.39+/-0.14 and 1.4+/-0.14 in Group I and 2.15+/-0.5, 1.48+/-0.23, 1.41+/-0.21 and 1.23+/-0.11 in Group II, respectively. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%). Both calcineurin inhibitors are effective and safe in KT. The higher rate of AR in Group II was related to more highly sensitized patients and the higher CMV infections was due to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. The same study will be continued to evaluate the long term effects of both drugs.

Prevalence of hepatitis C virus isolate genotypes from chronically infected Lebanese patients: a hospital-based study.

To assess percentages of hepatitis C virus (HCV) genotypes in infected Lebanese patients referred to St. George Hospital, Beirut, Lebanon, 77 infected cases were studied. Of those, 27 were hemodialysis patients. Genotyping was performed by nested PCR of the HCV core-region with specific primers, followed by DNA enzyme-immunoassay using HCV type and subtype-specific probes. Single genotype infections were detected in 52 patients (67.5%). In these cases, types 1, 2, 3 and 4 were detected in 19.5%, 32.5%, 5.1% and 10.4% of the cases respectively. Twenty-five (32.5%) samples showed mixed genotype infections. Single genotype distribution was significantly different among dialysis and non-dialysis patients. In the dialysis group, genotype 2 was predominant (80%, p < 0.001). In single HCV genotype-infected patients, subtype 1b was frequently detected in nondialysis cases (34.4%) whereas this genotype was found in only 5% of dialysis cases. Genotypes 5 and 6 were not detected in any of the cases studied. This pilot hospital-based study provides evidence for the diversity of HCV genotypes in the Lebanese population and establishes differences in distribution depending on the risk group.

Transcriptional and post-transcriptional mechanisms of glucocorticoid antiproliferative effects.

Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in treating organ transplantation rejection, autoimmune diseases, (hematological) cancers, and inflammatory disorders. GCs exert their effects through a multitude of mechanisms, the most significant of which is inhibition of cytokine production, and for some cytokines their effects on target cells. Paradoxically, GCs also upregulate the expression of (pro-inflammatory) high-affinity cytokine receptors on target cells in the face of lost ligand (cytokine) stimulation. GC inhibition of cytokine expression occurs at both transcriptional and post-transcriptional levels. GCs acted transcriptionally by binding their cytosolic receptor (GR), thereby facilitating its nuclear translocation and subsequent binding to the promoter region of cytokine genes on sites compatible with GC response element (GRE) motifs, which in turn directly or indirectly regulated gene expression. In addition to direct DNA binding, GCs acted post-transcriptionally by: (1) antagonism of nuclear factors required for efficient gene expression either directly or through induction of the expression of specific transcription factor antagonists, (2) altered Th lineage development by favouring the generation of (anti-inflammatory) Th2 cells and suppressing the induction or the activity of established (pro-inflammatory) Th1 cells, and (3) stimulating the expression of transforming growth factor (TGF)-beta, an immunosuppressive cytokine which inhibited cytokine production. However, these mechanisms are not mutually exclusive, since GCs may utilize more than one mechanism in exerting their anti-proliferative effect.