Kidney transplantation in children and adolescents: an analysis of United Network for Organ Sharing Database.

Specific pediatric allocation schemes can not only lead to minimization of waiting time, but also to better clinical outcomes for children with end-stage renal disease. The outcome of 4125 deceased donor kidney transplants (DDKT) aged 5-35 years were compared with those of 6456 living donor kidney transplants (LDKT) using univariate and multivariate Cox regression analyses. Unadjusted graft survival rates of DDKT were significantly lower than those of LDKT (hazards ratio [HR] = 1.53; P < .001). Chronic rejection was reported in 416 (10.1%) of 4125 in the DDKT group compared with 537 (8.3%) of 6456 in the LDKT group (P < .001). Among African American recipients, 67 (3.4%) grafts were lost due to noncompliance as a contributory cause of failure compared with 126 (1.5%) among other races (P < .001). A significantly lower incidence of noncompliance was observed in children (0.9%) compared with adolescents (2.2% in ages 10-14; P < .001) and high teens (2.0% in ages 15-20; P < .001). Multivariate analysis showed that adjusted graft survival rates of LDKT were superior to DDKT (HR = 1.22; P < .001) after adjusting for recipient race, recipient age, regraft status, and HLA mismatch. The differences of long-term graft survival rates between DDKT and LDKT have not been reduced (4% at 1 year, 10% at 3 years, and 12% at 5 years for unadjusted survival rates and 3% at 1 year, 6% at 3 years, and 9% at 5 years adjusted survival rates). In our analysis presented here the difference in graft survival between LDKT and DDKT has doubled compared with earlier analysis. Therefore, we recommend LDKT whenever possible as a first choice for pediatric transplant recipients.

Can machine perfusion decrease the likelihood of discard among biopsied kidneys?

Many factors, such as donor risk factors and renal function, have been shown to be associated with an increased likelihood of discard after recovering kidneys from deceased donors. When these factors are insufficient for assessment, renal biopsy is often performed at the time of harvest to assess suitability. Our aims were to identify factors that predict the discard of a biopsied kidney and to assess the impact of machine perfusion (MP) on kidney discard. We biopsied 678 kidneys from deceased donors aged >or=40 years from 2001 to 2006. We used a logistic regression model to estimate the adjusted odds ratios for kidney discard. Thirty-nine percent (n = 261) of biopsied kidneys were discarded. Kidneys with glomerulosclerosis (GS) > 20% had the highest likelihood of discard. Other significant predictors of discard included extreme donor age, final resistance (>40), atherosclerosis, interstitial fibrosis, arteriolosclerosis, and terminal serum creatinine value (SCr) > 1.5 mg/dL. MP kidneys (n = 69) were less likely to be discarded than cold storage (CS) kidneys after adjusting for other factors (adjusted odds ratio = .13, P < .001). In conclusion, abnormal biopsy findings were associated with the highest likelihood of discard. MP was used in only 10% of the cases; however, the use of MP was associated with a decreased likelihood of discard among biopsied kidneys.

Factors associated with discard of recovered kidneys.

We reviewed diseased donor (DD) kidney usage at a single Organ Procurement Organization in Southern California to more closely examine factors associated with discard. From 2001 to 2006, 3863 kidneys from 1959 DDs were recovered, but 454 (11.8%) were subsequently discarded. Among the discarded kidneys, 211 (46.5%) were discarded based upon biopsy findings, 19 (4.2%) due to anatomical abnormalities, 16 (3.5%) based on donor quality, and 14 (3.1%) because they were felt to be too old to be pumped. Multivariate logistic regression analysis was performed using significant prognostic factors upon univariate analyses. According to the magnitude of the adjusted odds ratio (AOR), significant prognostic factors for discard were extreme donor age (AOR = 24.1 of age 70-80 years, P < .001; AOR = 6.34 age 50-69 years, P < .001; AOR = 2.77 age 40-49 years, P < .001; and AOR = 3.09 age <10 years, P < .001 vs age 10-39 years), high final resistance (AOR = 8.86 of >40 vs others, P = .006), glomerulosclerosis (GS) > 20% (AOR = 5.94 vs GS 0%-5%/no biopsy, P < .001), severe atherosclerosis (AOR = 4.66, P = .003), abnormal anatomy (AOR = 2.7, P < .001), and moderate or severe arteriolosclerosis (AOR = 2.2 vs none/mild/no biopsy, P < .001). Among biopsy findings, the presence of GS > 20% was associated with the highest likelihood of discard. A high final resistance increased the likelihood of discard as well. In conclusion, these findings may help to set the groundwork toward a more uniform approach to organ utilization in donor service areas.

IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients.

Inosine 5'-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the rate-limiting step of the de novo pathway for purine synthesis and is a major target of the immunosuppressive drug mycophenolic acid (MPA). Few variants of the IMPDH1 gene have been reported. The objective of this study was to identify and characterize IMPDH1 variants to determine whether genetic variation contributes to differences in MPA response and toxicity in transplant patients. Seventeen genetic variants were identified in the IMPDH1 gene with allele frequencies ranging from 0.2 to 42.7%. In this study, 191 kidney transplant patients who received mycophenolate mofetil were genotyped for IMPDH1. Two single-nucleotide polymorphisms, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post-transplantation. Future studies of the multifactorial nature of acute rejection must consider IMPDH1 polymorphisms in MPA-treated patients.

Cytokine profiling of pulmonary aspergillosis.

Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.

Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation.

BACKGROUND: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4. AIM: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. PATIENTS AND METHODS: Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression. RESULTS: Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/+6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection. CONCLUSION: The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.

Donor CCR5 Delta32 polymorphism and outcome following cardiac transplantation.

BACKGROUND: Chemokines regulate the recruitment and trafficking of leukocytes during an immune response. Animal models have shown correlations between chemokine production and leukocyte infiltration during allograft rejection. Also, antagonism of chemokine receptors in transplant models has produced prolonged graft survival. Individuals homozygous for a 32 base pair deletion in the CC chemokine receptor 5 (CCR5) gene have an inactive receptor. Renal transplant recipients homozygous for the deletion have been shown to survive significantly longer than those heterozygous or homozygous for the wild type allele. CCR5 ligands are upregulated during allograft rejection aiding infiltration of leukocytes. We investigated the influence of CCR5Delta32 polymorphism on outcome following human cardiac transplantation. METHODS: Recipients and corresponding donors were genotyped for CCR5Delta32 polymorphism using polymerase chain reactions. RESULTS: We found no correlation between recipient genotype and outcome following transplantation. However, there was a significant correlation between donor genotype and mortality in patients transplanted for a nonischemic condition (DD = n/a, ID = 4%, II = 25%, P = .0014). CONCLUSIONS: The induction of CCR5 expression in endomyocardial biopsy tissue is known to correlate with leukocyte graft infiltration. We suggest that donor CCR5 may be more important for leukocyte trafficking during rejection than recipient CCR5 expression. The CCR5 gene is highly conserved, and due to the small population available for this study, more work is required from other centers.

CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology.

INTRODUCTION: Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. METHODS: We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. RESULTS: Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). CONCLUSION: Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.

The distribution of cardiac macrophages in myocardial ischaemia and cardiomyopathy.

AIMS: Recent evidence has implicated the macrophage as an effector cell in the inflammatory processes in transplant rejection, as well as cardiac disease, including coronary atherosclerosis. Although the latter is a vascular disease, the entire myocardium is affected. We have previously demonstrated the presence and distribution of macrophages in the 'normal' human heart. In this paper the distribution of myocardial macrophages, in the various chambers of the failing human heart, from cases of coronary atheroma and cardiomyopathy undergoing heart transplantation is documented. METHODS AND RESULTS: Tissue blocks were removed at specific sites taken from six cases with ischaemic heart disease (IHD) (four males, two females, age range 54-62 years), and four cases with idiopathic dilated cardiomyopathy (IDCM) (three males, one female, age range 18-49 years). These were compared with hearts from five cases of sudden death, unrelated to heart disease. Sections were stained with a CD68 pan macrophage marker. Positive cells were enumerated in 20 random fields. Results were analysed using a generalized linear modelling method using a Poisson distribution. Macrophages were identified within the interstitium and often close to blood vessels in all hearts. Macrophages from IHD hearts demonstrated the most intense staining and were often larger and more elongated than those found in 'normal' control hearts. Macrophages were also often degranulated and staining was diffuse in the interstitium. Overall, there were significantly more macrophages in most areas from IHD hearts than from IDCM hearts or control hearts (P < 0.001). CONCLUSIONS: Significantly more macrophages were found in all four chambers in diseased hearts compared with controls. Macrophage numbers were higher in the atria than in ventricles in the diseased myocardium. This study suggests selective recruitment of macrophages into the atria in the disease states studied.

Cytokine gene polymorphisms associated with symptomatic parvovirus B19 infection.

BACKGROUND: The immune system has been implicated in the pathogenesis of certain clinical manifestations of parvovirus B19 infection, including rash and arthralgia. Cytokines feature in the pathogenesis of parvovirus B19 infection, so inherited variability in cytokine responses to B19 infection might have a bearing on the symptomatology of parvovirus B19 infection. AIMS: To investigate the possible role of cytokine gene polymorphisms in the clinical manifestations of parvovirus B19 infection. METHODS: Thirty six patients with a variety of symptoms at acute infection and follow up (mean, 22.0 months) and controls (99-330, depending on the locus) were examined for the following cytokine polymorphisms: tumour necrosis factor alpha (TNF alpha), -308; interferon gamma (IFN-gamma), +874; interleukin 6 (IL-6), -174; IL-10, -592, -819, and -1082; and transforming growth factor beta1 (TGF beta 1), +869 (codon 10) and +915 (codon 25). RESULTS: The TNF alpha -308*A allele occurred in 13.9% of the parvovirus group compared with 27.0% of the control group (odds ratio (OR), 0.44; p = 0.02). The TGF beta 1 CG/CG haplotype was more frequent in the parvovirus group than in the controls (16.7% v 5%; OR, 4.8; p = 0.02). Within the B19 infected group, the TGF beta 1 +869 T allele was associated with skin rash at acute infection (p = 0.005), whereas at follow up the IFN-gamma +874 T allele was associated with the development of anti-B19 non-structural protein 1 antibodies (p = 0.04). CONCLUSIONS: The results of the present study suggest that inherited variability in cytokine responses may affect the likelihood of developing symptoms during parvovirus infection.

Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients.

African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-beta). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p < 0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p < 0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL-10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes.

Tumour necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction?

BACKGROUND: Tumour necrosis factor alpha (TNF alpha) is implicated in the pathophysiology of heart failure. Plasma TNF alpha is raised in patients with myocardial dysfunction in proportion to the symptoms. OBJECTIVE: To determine whether this genetic variant is over represented in heart transplant recipients. PATIENTS: 175 heart transplant recipients and a control group of 212 healthy volunteers were studied. The reason for transplantation was severe symptomatic myocardial dysfunction in all cases. METHODS: The TNF alpha genotype was determined by polymerase chain reaction and gel electrophoresis. The populations were compared for their fit to Hardy-Weinberg equilibrium by calculating the expected frequencies of each genotype and comparing them to the observed values. A chi(2) test was used to determine the significance of the difference between the observed and expected values. RESULTS: No differences were found in the frequency of the TNF2 allele between all heart transplant recipients taken together (54/175, 31%) and healthy volunteers (58/212, 27%). A higher proportion of TNF2 allele carriers was present in cardiac recipients with a pretransplant diagnosis of viral mediated or idiopathic heart failure than in those with ischaemic myocardial dysfunction (26/69 (37.7%) v 28/106 (26.4%), p = 0.03). PATIENTS with a non-ischaemic aetiology had a higher prevalence of TNF2 than healthy volunteers (26/69 (37.7%) v 58/212 (27%), p = 0.05). CONCLUSIONS: The TNF2 allele is overrepresented in patients with end stage non-ischaemic myocardial dysfunction. This may represent a genetic predisposition in a small subset of patients who could respond favourably to anti-TNF alpha treatment.

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production.

The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age- and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at -1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p = 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.

Influence of tumor necrosis factor-alpha gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in cardiovascular disease. Polymorphism of the TNF-alpha gene promoter region (position -308) influences an individual's production of TNF-alpha. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-alpha have been found in recipients with cardiac transplant vasculopathy and because TNF-alpha blockade can prevent the disease in rabbits, we investigated the effect of TNF-alpha promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients. METHODS: Using sequence-specific primers to the TNF-alpha gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-alpha genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. RESULTS: We found that 31.9% of recipients and 27.0% of donors were high TNF-alpha producers. The presence of the high-producing TNF-alpha allele led to an earlier diagnosis of vasculopathy; 3.42 years (+/- 91.3 days) vs 3.84 years (+/- 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (+/- 87.3 days) vs 3.78 years (+/- 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-alpha polymorphism had no effect on the freedom from vasculopathy when considering either recipient (p = 0.99) or donor (p = 0.86) TNF-alpha genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. CONCLUSIONS: Polymorphism at position -308 in the promoter region of the TNF-alpha gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.

Influence of TNFalpha gene polymorphisms on TNFalpha production and disease.

Tumor necrosis factor alpha (TNFalpha) is a potent inflammatory cytokine. In human, the TNFalpha gene is located within the highly polymorphic major histocompatibility complex (MHC) region on chromosome 6p21.3. TNF gene cluster contains many polymorphisms including microsatellites and single nucleotide polymorphisms (SNPs). Many of these polymorphisms were found to be in linkage disequilibrium with HLA class I and II alleles. Some of the TNFalpha gene polymorphisms were found to influence TNFalpha production in vitro, for example the -308 SNP. Many studies have shown that this SNP and others within the TNFalpha gene associate with different inflammatory conditions. Whether this phenomenon is due to the direct influence of the SNP in question and/or due to linkage disequilibrium with other polymorphisms within the TNFalpha gene or the HLA system is still controversial.

In vitro cytokine production of TNFalpha and IL-13 correlates with acute liver transplant rejection.

Individuals may differ in their capacity to produce cytokines. Since cytokines play a key role in allograft rejection, we investigated whether inter-individual differences in cytokine production by in vitro stimulated PBMC are related to the occurrence of acute liver transplant rejection. Our study group comprised 49 liver transplant recipients and 30 healthy individuals. Rejection, which occurred within one month after liver transplantation, was defined in 22 patients ("rejectors") as biopsy-proven rejection, treated with high dose prednisolone. Patients who never experienced rejection episodes were termed as "nonrejectors" (n=27). PBMC of healthy individuals and of liver transplant recipients, collected late after transplantation (mean 3.5 years), were cultured in the presence and absence of Concanavalin A. The production of TNF-alpha, IFN-gamma, IL-10, and IL-13 was measured in supernatant after 1, 2, 3, 4, and 7 days of cell culture. In cell culture, stimulated PBMC of rejectors were found to produce significantly higher levels of TNF-alpha, while there was a trend towards higher production of IFN-gamma and IL-10 as compared to nonrejectors. After grouping patients into high or low cytokine producers based upon reference levels of the healthy individuals using multivariate analysis it was found that occurrence of acute liver transplant rejection correlated to high production of TNF-alpha and low production of IL-13. After stimulated cell culture PBMC of liver transplant recipients show a differential production of TNF-alpha and IL-13 which is correlated with the occurrence of acute liver transplant rejection.

Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss.

Approximately one in 300 women experience recurrent pregnancy loss (RPL), the aetiology of which is unknown in at least 40% of cases. Previously, some studies have shown increased production of pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma) and reduced production of anti-inflammatory cytokines (interleukin-10) by circulating blood lymphocytes isolated from these patients when compared with controls. The reasons for this are unclear. The production of these cytokines are partly under genetic control. This study investigated whether polymorphisms in these three cytokine genes known to be associated with either high or low production, are associated with idiopathic RPL. No association was found. It may be that genetic factors are not a major determinant of cytokine production during pregnancy, or alternatively it may be that the observed differences in cytokine production by peripheral lymphocytes do not accurately indicate what is occurring at the local maternofoetal interface during successful and abortive pregnancies.

Transforming growth factor beta and myocardial dysfunction following heart transplantation.

OBJECTIVE: We analyzed the role of transforming growth factor-beta (TGF-beta), a fibrogenic cytokine, in the development of left ventricular diastolic dysfunction following heart transplantation. METHODS: We studied 152 heart transplant recipients who had survived for at least 24 months. We compared histopathological findings (staining of endomyocardial biopsy specimens using Hematoxylin Eosin and polyclonal antibodies), left ventricular function (Doppler echocardiography) and clinical course (NYHA status). Patients are classified into group A (n=56 recipients) with immunohistochemical TGF-beta staining score >7 and group B (n=96 recipients) with a staining score <7. RESULTS: Doppler echocardiographic evaluation demonstrated greater impairment of left ventricular diastolic function in recipients with higher TGF-beta staining score. The average mitral deceleration time was 129+/-6 ms for recipients group A compared to 167+/-15 ms in group B. While the mean isovolumic relaxation time was 65+/-8 ms for patients in group A compared with 82+/-6 ms for recipients in group B (P=0.0004 and 0.005, respectively). Immunohistochemical scoring correlated inversely with both mitral deceleration and isovolumic relaxation times (r=-0.74, P=0.0004 and r=-0.66, P=0.004, respectively). Mean NYHA status was 2.7+/-1.3 for group A compared to 1.17+/-0.4 in group B was (P=0.002). Five years follow-up revealed persistent left ventricular diastolic impairment for recipients with higher immunohistochemical staining score. Mitral deceleration time and isovolumic relaxation time were 118+/-11 and 62+/-7 ms for group A compared to 156+/-12 and 80+/-5 ms for group B, P=0.006 and P=0.01, respectively. The actuarial development of subsequent coronary artery disease (> 50% stenosis) was 17 and 29% for recipients in group A compared to 4 and 6% for recipients in group B at 3 and 5 years follow-up, respectively (P=0.01 and P=0.005, respectively). CONCLUSIONS: TGF-beta expression in cardiac allografts is associated with impaired graft function and limited survival. The pathogenesis of diastolic dysfunction may be an aberrant repair process following rejection due to increased TGF-beta expression in transplant recipients.