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Immunosuppression
Kinds of Immunosuppression Terms modified by Immunosuppression Selected AbstractsImmunosuppression in the northern leopard frog (Rana pipiens) induced by pesticide exposureENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2003Mary-Kate Gilbertson Abstract An injection study and a field study were used to investigate the hypothesis that environmental xenobiotics have the potential to alter the immune function of northern leopard frogs (Rana pipiens). Three assays, IgM-specific antibody response to keyhole limpet hemocyanin linked to dinitrophenyl (KLH-DNP), zymozan induced chemiluminescence (CL) of whole blood and the delayed-type hypersensitivity (DTH), were used to assay humoral, innate and cell-mediated immune endpoints. Sublethal doses of DDT (923 ng/g wet wt), malathion (990 ng/g wet wt), and dieldrin (50 ng/g wet wt) were used in the injection study. In all pesticide-injected groups, antibody response was dramatically suppressed, DTH reactions were enhanced, and respiratory burst was lower. When the order of administration of pesticides and antigens was reversed, no differences in immune function between the control and dosed groups were apparent, indicating that frogs exposed to pathogens prior to pesticide exposure can still respond. A field study found significant differences in immune function between frog populations in pesticide-exposed and pesticide-free locations. The antibody response and CL were suppressed and the DTH enhanced in frogs from Essex County (ON, Canada). Overall, the results suggest that exposure to these pesticides can cause both stimulatory and suppressive immune changes in adult frogs and is doing so in wild populations. [source] Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010William F. Carson Abstract Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4+ T-cell responses remains unclear. In the present study, CD4+ T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4+CD62L+ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4+CD62L+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the TH1 or TH2 lineage. Repressive histone methylation marks were also evident at promoter regions for the TH1 cytokine IFN-, and the TH2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that CD4+ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription. [source] Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells,HEPATOLOGY, Issue 2 2006Yao-Ming Wu Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression. It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing long-term survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410,419.) [source] Th1 cytokine,induced downregulation of PPAR, in human biliary cells relates to cholangitis in primary biliary cirrhosis,HEPATOLOGY, Issue 6 2005Kenichi Harada Peroxisome proliferator-activated receptor-, (PPAR,) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPAR, ligands can ameliorate clinical severity by downregulating the expression of proinflammatory cytokines. Primary biliary cirrhosis (PBC) is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. Unusual immune responses to infectious agents are suspected to underlie its etiopathogenesis. We examined the significance of PPAR, in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-,B) DNA-binding assays to clarify the intrahepatic distribution of PPAR, and the regulation of PPAR, by inflammatory cytokines and PPAR, ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPAR, protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPAR, protein and mRNA was reduced in damaged bile ducts. PPAR, expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-, (Th1-type). PPAR, ligand negatively modulated lipopolysaccharide-induced NF-,B activation. Moreover, this inhibitory effect of PPAR, ligand was attenuated by pretreatment with IFN-,. In conclusion, PPAR, may be important to maintain homeostasis in the intrahepatic biliary epithelium, and its reduction in the bile ducts of PBC liver may be associated with the Th1-predominant milieu and with the development of chronic cholangitis in PBC. Immunosuppression using PPAR, ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC. (HEPATOLOGY 2005;41.) [source] Long-term clinical outcome of living-donor liver transplantation for primary biliary cirrhosisHEPATOLOGY RESEARCH, Issue 2007Etsuko Hashimoto Aim:, We described the recurrence of primary biliary cirrhosis (PBC) after living donor liver transplantation (LDLT) (Liver Transplantation, 7, 2001: 588). However, since the follow-up period in that study was insufficiently long (median 35.5 months), we performed a long-term study to further characterize recurrence of PBC after LDLT. Patients:, From 1991 to 2006, 15 patients with end-stage PBC underwent LDLT at Tokyo Women's Medical University. Of these patients, we studied 8 PBC patients (age 29 to 51 years, all females) who survived LDLT for more than 5 years. The follow-up period for these patients ranged form 68 to 120 months. Immunosuppression was maintained with tacrolimus and prednisone. Laboratory examinations performed in every patient and donor before LDLT included routine biochemical studies, antimitochondrial antibody (AMA) by immunofluorescence (IF), anti-M2 by enzyme-linked immunosorbent assay as well as antinuclear antibody (ANA) by IF, and immunoglobulin. After LDLT, the same laboratory examinations were performed in patients every 6 months. Liver biopsy was performed when patients exhibited clinical or biochemical signs of graft dysfunction. In addition, protocol biopsy was performed every 1 to 2 years after LDLT. Results:, At the time of LDLT, all patients had end-stage cholestatic liver failure. Seven patients were positive for AMAand anti-M2 while 1 patient was negative for these markers but strongly positive for ANA. Donors were blood relatives in 6 cases, and 2 donors who were not blood relatives still exhibited multiple HLA matches with the recipients. At the end of the study in May 2006, all patients were doing well. On laboratory examination, mild abnormal liver function test results were found in 4 patients: 3 were probably due to recurrence of PBC, 1 resulted from nonalcoholic steatohepatitis. Comparison of the AMA titer between before LDLT and the most recent follow-up visit showed an increase in three patients, a decrease in two patients and no change in three patients. In contrast, the ANA titer increased in five patients. Histologically, strong evidence of recurrent PBC was found in 4 patients, and findings compatible with PBC were present in 2 additional patients. Conclusions:, Although the number of our patients is small, our findings confirm that PBC can recur at high frequency after LDLT. However, this complication has not developed to advanced stages and has not caused appreciable symptoms in our patients, all of whom have a good quality of life. [source] Rapid progression of small cell carcinoma in a renal transplant recipientINTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2006ANTTI RANNIKKO Abstract, Immunosuppression is thought to be responsible for the increased incidence of tumor development after organ transplantation. Natural history of these tumors may be more aggressive than would be expected for a similar tumor in a patient without transplant. We describe the fulminant course of small cell carcinoma, likely of prostatic origin, in a kidney transplant patient. Small cell carcinoma (SCC) and especially SCC of the prostate is an aggressive and rare type of tumor. Due to its rarity, only case reports have been published. To our knowledge, this is the first case of SCC, likely of prostatic origin, in an organ transplant recipient (OTR). The case illustrates the aggressiveness of the disease as reflected by its fulminant progression, which may have been further accentuated by the immunosuppression. [source] Immunosuppression with FK506 Increases Bone Induction in Demineralized Isogeneic and Xenogeneic Bone Matrix in the RatJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2000Dr. Gregor Voggenreiter Abstract The aim of the present study was to investigate a systemic induction of bone formation in rats by immunosuppression with FK506 (1 mg/kg body weight intraperitoneally [ip]) in a model of osteoinduction of isogeneic and xenogeneic demineralized bone matrix (DBM) for a period of 28 days. In particular, alterations of in vitro cytokine synthesis and changes of lymphocyte subsets were studied. DBM was implanted intramuscularly in the abdominal wall of Lewis rats (seven per group). Blood was sampled on days ,7, 0, 7, and 28 for determination of in vitro tumor necrosis factor , (TNF-,) synthesis and lymphocyte subsets by flow cytometry (CD3+, CD4+, CD8+, CD45+, ED9+, and Ia+ antibodies). Ossicles of de novo formed bone and the tibias were removed on day 28 after double tetracycline labeling for histomorphometric analysis. Immunosuppression with FK506 significantly decreased lipopolysaccharide (LPS)-stimulated in vitro cytokine synthesis after 7 days and 28 days (p < 0.05). Compared with control animals FK506 treatment significantly increased the volume of induced bone in isogeneic (2.1 ± 0.3 mm3 vs. 10.8 ± 0.9 mm3) and xenogeneic (0 mm3 vs. 4.7 ± 0.8 mm3) DBM. Bone histomorphometry of the tibias revealed that immunosuppression increased both bone formation and bone resorption, accompanied by a significant reduction in the relative trabecular area (Tb.Ar). FK506 caused a decrease in the counts of CD8+ T cells probably because of destruction or dislocation of these cells. This suggests that the amount of CD8+ cells and the degree of T cell activation in terms of mean fluorescence intensity (MFI) may be associated with bone metabolism. In support of this, statistical analysis revealed a significant positive correlation between parameters of bone formation as well as bone resorption and the CD4+/CD8+ ratio. There was a significant negative correlation between parameters of remodeling of the metaphysis of the tibia and induced bone volume (BV), respectively, and MFI values of CD3+/Ia+ cells. These findings suggest an important role of T lymphocytes in bone formation and bone resorption in vivo. FK506 caused a marked increase of bone formation in DBM. However, the conclusion that immunosuppression increases fracture healing warrants further investigation. [source] Gingival and other oral manifestations in measles virus infectionJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 7 2003Joseph Katz Abstract Background: Measles is a highly contagious, viral infectious disease affecting mainly children and young adults. It is characterized by high fever, maculopapular rash, keratoconjunctivitis and pathognomonic oral Koplik's spots. Methods: During an outbreak of measles among soldiers in the Israeli military, patients were referred to one medical center where they were also examined for oral signs and symptoms of their illness. Results: We present a case of measles infection with distinct oral findings. These included Koplik's spots, various forms of ulcerations of the free mucosa, -like gingivitis and pericoronitis. All oral lesions resolved after cessation of systemic illness. Conclusions: The measles virus is associated with a transient inhibition of the host response. Immunosuppression may create the necessary condition for the proliferation of pathobacteria associated with the observed pericoronitis and the other gingival lesions. Zusammenfassung Hintergrund: Masern sind eine hochgradig ansteckende virale Infektion, die vorwiegend Kinder und junge Erwachsene befällt. Sie ist charakterisiert durch hohes Fieber, makulopapulären Ausschlag, Keratokonjunktivitis und pathognomonische orale Koplik-Flecken. Zielsetzung: Beschreibung der oralen und gingivalen Manifestationen des Masern-Virus bei jungen Erwachsenen. Methoden: Während einer Masernepidemie bei Soldaten der israelischen Streitkräfte wurden die Patienten an ein Medizinisches Zentrum überwiesen, wo sie auf orale Zeichen und Symptome ihrer Erkrankung untersucht wurden. Ergebnisse: Es wird ein Fall von Masern mit speziellen oralen Symptomen gezeigt: Koplik-Flecken, verschiedene Formen von Ulzerationen der Alveolarmukosa, der NUG ähnliche Gingivitis und Pericoronitis. Alle oralen Läsionen heilten nach Ende der systemischen Erkrankung aus. Schlussfolgerungen: Eine Infektion mit dem Masern-Virus geht mit einer vorübergehenden Schwächung der Wirtsabwehr einher. Diese Immunsuppression könnte die notwendigen Bedingungen für das Wachstum von pathogenen Keimen schaffen, die mit den beobachteten Perikoronitiden und gingivalen Läsionen assoziiert waren. Résumé La rougeole est une maladie infectieuse virale très contagieuse qui affecte essentiellement les enfants et les jeunes adultes. Elle est caractérisée par la haute température, une éruption maculo-papulaire, une kérato-conjonctivite et des spots de Koplik buccaux pathognomoniques. Durant une épidémie de rougeole parmi les soldats de l'armée israélienne, des patients ont été référés vers un centre médical où ils ont également été examinés pour les signes buccaux et les symptômes de leur maladie. Un cas d'infection de rougeole avec des découvertes buccales distinctes est présenté. Elles comprennent : les spots de Koplik, des formes variées d'ulcérations de la muqueuse libre, une gingivite genre gingivite nécrotique et une péricoronarite. Toutes les lésions buccales ont disparu après la fin de la maladie systémique. Le virus de la rougeole est associéà une inhibition transitoire de la réponse immunitaire. L'immunosuppression peut créer la condition nécessaire pour la prolifération de bactéries pathogènes associées avec la péricoronarite observée ainsi que les autres lésions gingivales. [source] Fatal HHV6 infection in an immunocompromised patient presenting with skin involvementJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2010Anjela Galan Infection with human herpesvirus-6 (HHV6) has a broad distribution in the human population, with a seroprevalence approaching 100% worldwide. Primary infection takes place during childhood, after which the virus remains latent mostly in lymphocytes and monocytes at various sites. Immunosuppression can result in viral reactivation, associated with clinical sequelae and even death. We report a case of a disseminated HHV6 infection in a 53-year-old patient, who was immunocompromised after allogeneic bone marrow transplant treatment for acute lymphocytic leukemia. Initially, he presented with a macular eruption of the skin, followed by involvement of other sites. Histopathologic analysis of skin biopsies revealed superficial perivascular large atypical mononuclear cells with intranuclear and intracytoplasmic inclusions. Most affected cells labeled with antibodies to CD3 and CD43 as lymphocytes, and some labeled with CD68 as macrophages. Polymerase chain reaction (PCR) studies of the blood, skin, liver, colon, cerebrospinal fluid and brain were positive for HHV6 virus. Additionally, the serologic titers for HHV6 were high. Viral particles were also detected by electron microscopy (EM) in the colon. Although rare, HHV6 virus may be an important pathogen in immunocompromised patients, and may present initially in the skin. Awareness of this infection is critical to diagnosis in acute settings. Galan A, McNiff JM, Nam Choi J and Lazova R. Fatal HHV6 infection in an immunocompromised patient presenting with skin involvement. [source] Apparent Reactivation of a Fibrohistiocytic Proliferation with Features of Dermatofibroma and Dermatomyofibroma Following Systemic ImmunosuppressionJOURNAL OF CUTANEOUS PATHOLOGY, Issue 1 2005W.A. High A 41 year-old man presented with an atrophic, hyperpigmented plaque on the right lower abdomen present since"birth". He denied any prior activity at the site, and had been told it was a "scar" from a prenatal insult. Six months earlier, he developed idiopathic focal sclerosing glomerulonephritis and was placed on 70 mg prednisone per day. He had not demonstrated evidence of lupus eythematosus. Shortly after beginning this regimen, erythematous and tender papules developed around the quiescent plaque. He had tapered his prednisone dose to 60 mg per day, but additional papules continued to erupt. An ellipse biopsy was performed which included a portion of the atrophic plaque and several surrounding papules. Histological examination revealed a proliferation of fibrohistiocytes between and amongst collagen bundles. In some areas, fibrohistiocytes entrapped collagen in a fashion reminiscent of a dermatofibroma. In other areas, particularly that of the atrophic plaque, the fibrohistiocytes were less numerous and more delicate in appearance. Scattered rudimentary fascicles were demonstrated. Adnexal structures were preserved. Immunohistochemical staining revealed the fibrohistiocytes to be positive for factor XIIIa and actin, but negative for desmin, CD34, S-100, procollagen I, and CD68. This lesion demonstrated unique clinical/histiological aspects not well characterized in the literature. [source] Tissue tropism of nervous necrosis virus (NNV) in Atlantic cod, Gadus morhua L., after intraperitoneal challenge with a virus isolate from diseased Atlantic halibut, Hippoglossus hippoglossus (L.)JOURNAL OF FISH DISEASES, Issue 8 2009K Korsnes Abstract Atlantic cod, Gadus morhua, averaging 100 g, were experimentally challenged by intraperitoneal injection of nervous necrosis virus (NNV) originating from Atlantic halibut. Cod tissues, including blood, gill, pectoral fin, barbel, ventricle, atrium, spleen, liver, lateral line (including muscle tissue), eye (retina) and brain, were sampled at day 25 and 130 and investigated by real-time RT-PCR for the presence of NNV. Relative quantifications at day 130 were calculated using the 2,,,Ct method. Immunosuppression by injection of prednisolone-acetate was introduced for a 30-day period, and tissue sampled at day 180 and relative quantification estimated. No mortality or clinical signs of disease were observed in the challenged group. The challenge resulted in detection of NNV in blood, spleen, kidney, liver, heart atrium and heart ventricle at day 25, and by the end of the experiment NNV showed a clear increase in brain and retina, suggesting these to be the primary tissues for viral replication. There was no increase in the relative amount of NNV in blood, atrium, ventricle, spleen, liver and kidney. Corticosteroid implants resulted in a weak increase in virus RNA in spleen, kidney, liver and brain. These findings suggest that Atlantic cod is susceptible to infection with NNV from halibut. The observed tissue tropism patterns suggest an initial viraemic phase, followed by neurotrophy. Head-kidney is the best tissue identified for possible NNV detection by non-lethal biopsy, but detection was not possible in all injected fish. [source] Human papillomavirus infection and cervical abnormalities in Nairobi, Kenya, an area with a high prevalence of human immunodeficiency virus infectionJOURNAL OF MEDICAL VIROLOGY, Issue 5 2008Rika Yamada Abstract Human papillomavirus (HPV) infection and cervical abnormalities, and their association with human immunodeficiency virus (HIV) infection were studied in 488 women who visited a health center in Nairobi. PCR-based HPV and cervical cytology tests were carried out on all participants, and peripheral CD4+ T cells and plasma HIV RNA were quantitated in HIV positive women. HIV were positive in 32% (155/488) of the women; 77% of these were untreated, and the others had been treated with anti-retroviral drugs within 6 months. Cervical HPV infection was detected in 17% of HIV negative and 49% of HIV positive women. Low-grade squamous intraepithelial lesions were observed in 6.9% of HIV negative and 21% of HIV positive women, while high-grade squamous intraepithelial lesions and cancer were seen in 0.6% and 5.8%, respectively. Multivariate analysis revealed that HIV and HPV infections were associated with each other. Cervical lesions were significantly associated with high-risk HPVs and with HIV infection, depending on HPV infection. HPV infection increased in accordance with lower CD4+ T cell counts and higher HIV RNA levels, and high-grade lesions were strongly associated with high-risk HPV infection and low CD4+ T cell counts. Immunosuppression as a result of HIV infection appears to be important for malignant progression in the cervix. Nationwide prevention of HIV infection and cervical cancer screening are necessary for the health of women in this area. High-risk HPV infection and low CD4+ T cell counts are the risk factors for cervical cancer. J. Med. Virol. 80:847,855, 2008. © 2008 Wiley-Liss, Inc. [source] Inhibition of Hematopoietic Progenitor Cell Proliferation by Ethanol in Human Immunodeficiency Virus Type 1 Tat-Expressing Transgenic MiceALCOHOLISM, Issue 3 2001Om Prakash Background: A number of hematological abnormalities are associated with both human immunodeficiency virus type 1 (HIV-1) infection and alcohol abuse. There is little information on how alcohol abuse might further influence the survival and growth of hematopoietic progenitors in HIV-infected individuals in the presence of immune system abnormalities and anti-HIV drugs. Because there is evidence that viral transactivator Tat itself can induce hematopoietic suppression, in this study we examined the role of ethanol as a cofactor in transgenic mice that expressed HIV-1 Tat protein. Methods: Tat transgenic mice and nontransgenic littermates were given ethanol (20% v/v) and the anti-HIV drug 3,-azido-3,-deoxythymidine (AZT; 1 mg/ml) in drinking water. Immunosuppression in mice was induced by weekly intraperitoneal injections of anti-CD4 antibody. Hematopoiesis was examined by erythroid colony forming unit (CFU-E) and granulocyte/macrophage colony-forming unit (CFU-GM) assays of the bone marrow progenitor cells. Results: Administration of ethanol for 7 weeks resulted in a 50% decrease in the proliferative capacity of CFU-E- and CFU-GM-derived progenitors from transgenic mice compared with that of ethanol-treated nontransgenic controls. Similar decreases also were observed in transgenic mice treated with AZT or a combination of AZT and ethanol. Furthermore, ethanol and AZT were significantly more toxic to the granulopoietic progenitors (40,50% inhibition) than to the erythropoietic progenitors (10,20% inhibition) in Tat transgenic mice. Although a 10 day exposure of Tat transgenic and nontransgenic mice to a combination of ethanol and AZT had no suppressive effect on the erythropoietic and granulopoietic progenitor cells, there was a marked decrease (40,60%) in CFU-GM in mice made immunodeficient by CD4+ T-lymphocyte depletion. The ethanol-treated Tat transgenic mice but not the nontransgenic littermates also showed a significant decrease (25%) in CFU-GM. Conclusion: Our in vivo study strongly suggests that ethanol ingestion in HIV-1-infected individuals, particularly those on antiretroviral drugs, might increase bone marrow toxicity and contribute to HIV-1-associated hematopoietic impairment. [source] Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2010M. A. Smith Aliment Pharmacol Ther 2010; 32: 119,130 Summary Background, Immunosuppression is a risk factor for carcinogenesis. Thiopurines specifically contribute to this. As thiopurines are used more aggressively in the treatment of IBD, it is likely that we will see more thiopurine-related malignancy. Aim, To review the literature, exploring how immunosuppression, thiopurines specifically, might cause cancer and which malignancies occur in practice, placing specific emphasis on IBD cohorts. Methods, Search terms included ,malignancy',cancer',azathioprine',mercaptopurine',tioguanine (thioguanine)',thiopurine' and ,inflammatory bowel disease',Crohn's disease',ulcerative colitis'. We also searched for specific cancers (lymphoma, colorectal cancer, skin cancer, cervical cancer) and reviewed the reference lists of the articles detected. Results, Immunosuppression is associated with an increased risk of cancer. Thiopurines are associated with specific additional risks. In IBD cohorts, very few thiopurine-related malignancies have been reported. However, studies suggest a relative risk of 4,5 for lymphoma. This still translates into a low actual risk, (one extra lymphoma in every 300,1400 years of thiopurine treatment). Conclusions, Whilst we must be aware of this risk and counsel our patients appropriately, thiopurines remain a mainstay of IBD therapy. We present practical advice aimed at minimizing our patients' risk of developing malignancy, whilst optimizing the benefits that thiopurines can provide. [source] Immunosuppression, cancer, and the long-term outcomes after liver transplantation: Can we do better?,LIVER TRANSPLANTATION, Issue 7 2010James M. Abraham No abstract is available for this article. [source] Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: Results of a prospective randomized studyLIVER TRANSPLANTATION, Issue 12 2008Laura Lladó The purpose of this study was to evaluate the influence of a steroid-free immunosuppression on hepatitis C virus (HCV) recurrence. A total of 198 liver transplantation (LT) patients were randomized to receive immunosuppression with basiliximab and cyclosporine, either with prednisone (steroid [St] group) or without prednisone (no steroids [NoSt] group). The group of 89 HCV-infected patients was followed up with protocol biopsies for 2 years after LT. This group of HCV patients are the patients evaluated in the present study. The rejection rate was 19% (St: 21% versus NoSt: 17%; P = 0.67). Patients in the St group had a slightly higher rate of bacterial infections (59% versus 38%; P = 0.05). Almost all patients had histological HCV-recurrence (St: 39/40 (97%) versus NoSt: 40/41 (97%); P = 1). The percentage of accumulated biopsies with grade 4 portal inflammation at 6 months, 1 year, and 2 years were, 23%, 49%, and 49% in the NoSt group, compared to 33%, 55%, and 69% in the St group, respectively (P = 0.04 at 2 years). The percentage of accumulated biopsies with grade 3 or 4 fibrosis at 6 months, 1 year, and 2 years were 0%, 8%, and 22% in the NoSt group, compared to 8%, 19%, and 31% in the St group, respectively. Immunosuppression without steroids in HCV patients is safe, reduces bacterial infections and metabolic complications, and improves histological short-term evolution of HCV recurrence. Liver Transpl 14:1752,1760, 2008. © 2008 AASLD. [source] Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patientsLIVER TRANSPLANTATION, Issue 5 2007Isabelle Morard Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 ± 10 yr) after a median delay of 19.4 months (range 0.2,173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 ± 11 months. Median SRL dosage and trough levels were 2.4 ± 1.3 mg and 8.1 ± 2.7 ,g/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement. Liver Transpl 13:658,664, 2007. © 2007 AASLD. [source] Immunosuppression for liver transplantation in HCV-infected patients: Mechanism-based principlesLIVER TRANSPLANTATION, Issue 11 2005Bijan Eghtesad We retrospectively analyzed 42 hepatitis C virus (HCV)-infected patients who underwent cadaveric liver transplantation under two strategies of immunosuppression: (1) daily tacrolimus (TAC) throughout and an initial cycle of high-dose prednisone (PRED) with subsequent gradual steroid weaning, or (2) intraoperative antithymocyte globulin (ATG) and daily TAC that was later space weaned. After 36 ± 4 months, patient and graft survival in the first group was 18/19 (94.7%) with no examples of clinically serious HCV recurrence. In the second group, the three-year patient survival was 12/23 (52%), and graft survival was 9/23 (39%); accelerated recurrent hepatitis was the principal cause of the poor results. The data were interpreted in the context of a recently proposed immunologic paradigm that is equally applicable to transplantation and viral immunity. In the framework of this paradigm, the disparate hepatitis outcomes reflected different equilibria reached under the two immunosuppression regimens between the relative kinetics of viral distribution (systemically and in the liver) and the slowly recovering HCV-specific T-cell response. As a corollary, the aims of treatment of the HCV-infected liver recipients should be to predict, monitor, and equilibrate beneficial balances between virus distribution and the absence of an immunopathologic antiviral T-cell response. In this view, favorable equilibria were accomplished in the nonweaned group of patients but not in the weaned group. In conclusion, since the anti-HCV response is unleashed when immunosuppression is weaned, treatment protocols that minimize disease recurrence in HCV-infected allograft recipients must balance the desire to reduce immunosuppression or induce allotolerance with the need to prevent antiviral immunopathology. (Liver Transpl 2005;11:1343,1352.) [source] Mucocutaneous Findings in Pediatric AIDS Related to Degree of ImmunosuppressionPEDIATRIC DERMATOLOGY, Issue 4 2003Siriwan Wananukul The immunologic categories according to the 1994 revised pediatric human immunodeficiency virus (HIV) classification, based on CD4-positive percentage of the total lymphocyte count, is classified into three categories: no evidence of suppression (,25%), moderate suppression (15,24%), and severe suppression (1,14%). Our objective was to determine the prevalence of mucocutaneous findings in pediatric acquired immunodeficiency syndrome (AIDS) related to the degree of immunosuppression. We prospectively examined 120 children less than 13 years of age who were born to HIV-seropositive women and developed definite HIV infection. The prevalence of mucocutaneous findings in those children who had severe, moderate, and no evidence of immunosuppression were 62%, 43%, and 20%, respectively. The mucocutaneous findings in patients in the moderate and severe suppression groups were significantly more common than in patients without evidence of immunosuppression (p < 0.001). In the moderate immunosuppression group, 11% had two mucocutaneous findings while 21% in the severe immunosuppression group had two or more mucocutaneous findings. The most common mucocutaneous finding was oral candidiasis (33%), which had a mean corresponding CD4 percentage of the total lymphocyte count of 11.3%. Herpes zoster was found in 6% of the patients (mean CD4 percentage of the total lymphocyte count = 13.5%). Chronic herpes simplex virus (HSV) stomatitis was found in 3% of the patients (mean CD4 percentage of the total lymphocyte count = 3%). Mucocutaneous manifestations are common in pediatric AIDS. The majority of these findings have an infectious etiology. The prevalence increases as the CD4-positive percentage of the total lymphocyte count decreases. More than one mucocutaneous finding can be found at the same time in patients with moderate or severe immunosuppression. [source] Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 1 2010Carlos E. Araya Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients. Pediatr Transplantation 2010: 14: 145,150. © 2009 Wiley Periodicals, Inc. Abstract:, BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2,3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30,60 ,g/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients. [source] Post-transplant lymphoproliferative disorder following pediatric heart transplantationPEDIATRIC TRANSPLANTATION, Issue 1 2006Fernando Mendoza Abstract:, Immunosuppression after heart transplantation is implicated in development of post-transplant lymphoproliferative disorder (PTLD). Despite a higher prevalence of PTLD in children, there is scarce knowledge about incidence, pathophysiologic mechanisms and risk factors for PTLD in pediatric recipients of cardiac allografts. We examined retrospectively the medical records of all 143 pediatric patients (mean age 9.2 ± 6.1 yr) who received donor allografts between 1984 and 2002 and survived over 30 days. Five children (3.5%) developed PTLD over a mean follow-up period of 41.1 ± 46.0 months. Time from transplant to diagnosis of PTLD ranged from 3.9 to 112 months (mean 48.0 ± 41.9 months). Excluding PTLD, no other malignancies were found in this population. Actuarial freedom from PTLD was 99.2%, 99.2% and 96.2% at 1, 2, and 5 yr, respectively. Children who developed PTLD were more likely (by univariate analysis) to have been Rh negative (p = 0.01), Rh mismatched (p = 0.003), Epstein,Barr virus (EBV) seronegative (p = 0.001) and transplanted for congenital heart disease (p < 0.02). PTLD was associated with significant morbidity and mortality with a mean survival following diagnosis of 21.2 months. PTLD is a serious complicating outcome of cardiac transplantation that occurs in approximately 3.5% of children. Aside of immunosuppression, risk factors in this series for developing PTLD include EBV seronegativity and Rh negative status and mismatch. Non-hematogenous malignancies are rare in light of short allograft half-life. [source] EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantationPEDIATRIC TRANSPLANTATION, Issue 3 2004Clotilde Des Robert Abstract:, A 4-year-old boy presented 14 months after liver and small bowel transplantation with fever, diarrhea, elevated liver enzymes, thrombocytopenia and autoantibodies. Total gammaglobulins level was normal but the level of plasma IgA1 was very high. The blood PCR for Epstein,Barr virus (EBV) was negative. The ileal biopsy disclosed a lymphoplasmacytic infiltration. The EBER probe was negative on the small bowel biopsies. The child was considered as suffering from a non-EBV-induced posttransplant lymphoproliferative disorder (PTLD). The high IgA level was presumed to be secreted by proliferating plasma cells in the transplanted bowel. Immunosuppression was reduced; but the efficacy was incomplete and an anti-CD20 antibody was added. There was complete resolution of symptoms and normalization of the IgA level. As IgA1 is mostly of intestinal origin, this unusual presentation of PTLD should lead to a high suspicion of a small bowel proliferating process. [source] Hyperhomocysteinemia in pediatric and young adult renal transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 2 2004Amir Belson Abstract:, Hyperhomocysteinemia (HHcy) has been recently identified as an important and reversible cardiovascular risk factor in adult and pediatric renal transplant recipients. A retrospective cross-sectional analysis of 70 pediatric and young adult renal transplant recipients was performed to determine the prevalence, and important clinical and laboratory correlates of HHcy. Total homocysteine concentration, free and protein bound, was determined by fluorescence polarization immunoassay using an IMX analyzer. Hyperhomocysteinemia was defined as a serum homocysteine (Hcy) level above the 95th percentile for age. Fifty-four of 70 patients (77%) had HHcy. Comparison of patients with HHcy with patients without HHcy demonstrated no statistical difference in age (p = 0.35), gender (p = 0.76) or donor type (p = 0.20). Patients with HHcy had significantly lower calculated creatinine clearance values (Ccr) (p = 0.02), 67.3 ± 21.2 mL/min/1.73 m2 vs. 90.7 ± 32.3 mL/min/1.73 m2 for patients without HHcy. Immunosuppression did not correlate with the diagnosis of HHcy. Stepwise logistic regression identified patient age (0.18, p = 0.013) and Ccr (,0.04, p = 0.011) as significant variables. In conclusion, HHcy is more common than expected in pediatric renal transplant recipients. Patients with Ccr <80 mL/min/1.73 m2 were statistically more likely to have a diagnosis of HHcy. We recommend that Hcy levels should be evaluated in this high risk population. [source] Unusual evolution of an Epstein,Barr virus-associated leiomyosarcoma occurring after liver transplantationPEDIATRIC TRANSPLANTATION, Issue 5 2001Bénédicte Brichard Abstract: We report the case of a child who developed, 2 yr after orthotopic liver transplantation (OLTx) for biliary atresia, a multi-focal hepatic tumor with lymphonodular metastases, identified as an Epstein,Barr virus (EBV)-associated leiomyosarcoma. Chemotherapy was given without tumor response. Subsequently, slow growth of the tumor was observed. Immunosuppression was tapered and stopped 9 yr after transplantation. At the present time, 12 yr after the discovery of the first hepatic lesions, the patient is alive and completely symptom-free, the abdominal masses are stable, and liver function tests are completely normal. Smooth muscle tumors are increasingly recognized in children with various immunodeficiencies occurring after organ transplantation. This unusual evolution of a clinically aggressive tumor into a stable disease after restoration of immunity confirms that the immune status of the patient is a crucial factor. [source] Mixed chimerism and graft failure following conditioning with the fludarabine and cyclophosphamide nonablative regimen; Conversion to full donor chimerismAMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2007Anand P. Jillella Abstract Twenty-one patients with hematologic malignancies were treated with the fludarabine (120,125 mg/m2) and cyclophosphamide (120 mg/kg) nonmyeloablative conditioning regimen. Graft versus host disease (GVHD) and graft rejection prophylaxis was with tacrolimus and mycophenolate mofetil. Thirteen of the 21 patients (62%) had mixed chimerism (,,90% donor cells) at day 60 and 11 (52%) of these patients had mixed chimerism which persisted until day 100. Immunosuppression was discontinued in 12 of 13 patients and two of them converted to full chimerism by day 100. Eight patients received a donor lymphocyte infusion (DLI) and five of them converted to full donor chimerism with DLI alone. Two patients were given GM-CSF in addition to a DLI with conversion to full donor chimerism. Three patients (14%) had graft failure requiring a second transplant using fludarabine (125 mg/m2) and melphalan (140 mg/m2). With a median followup of 2.8 years, 15 patients are alive,one with disease and 14 with no disease. Two patients died of acute GVHD, one of chronic GVHD, and three due to progressive disease. We conclude that the nonmyeloablative fludarabine/cyclophosphamide regimen results in a significant incidence of mixed chimerism and graft rejection but is well tolerated. We suggest a more intense regimen, such as fludarabine and melphalan, be used in patients with a high risk of early disease progression to establish early engraftment and graft versus tumor effect. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source] UV-induced Immunosuppression in the Balance,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2008Frank R. De Gruijl Around 1980, experiments with hairless mice showed us that UV-induced actinic keratoses (AK) and ensuing skin carcinomas did not arise independently: the rate of occurrence in one skin area was increased considerably if AKs had already been induced separately in another distant skin area, i.e. a systemic effect. The ground laying work of Margaret Kripke in the 1970s provided a fitting explanation: UV-induced immunosuppression and tolerance toward the UV-induced tumors. From Kripke's work a new discipline arose: "Photoimmunology." Enormous strides were made in exploring and expanding the effects from UV carcinogenesis to infectious diseases, and in elucidating the mechanisms involved. Stemming from concerns about a depletion of the ozone layer and the general impact of ambient UV radiation, the groups I worked in and closely collaborated with explored the anticipated adverse effects of UV-induced immunosuppression on healthy individuals. An important turning point was brought about in 1992 when the group of Kevin Cooper reported that immunosuppression could be induced by UV exposure in virtually all human subjects tested, suggesting that this is a normal and sound physiological reaction to UV exposure. This reaction could actually protect us from illicit immune responses against our UV-exposed skin, such as observed in idiopathic polymorphic light eruption. This premise has fruitfully rekindled the research on this common "sun allergy," affecting to widely varying degrees about one in five Europeans with indoor professions. [source] Topically Applied Eicosapentaenoic Acid Protects Against Local Immunosuppression Induced by UVB Irradiation, cis -Urocanic Acid and Thymidine Dinucleotides,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2001Ralf M. W. Moison ABSTRACT UVB-induced immunosuppression, a promoter of photocarcinogenesis, involves the formation of pyrimidine dimers and cis -urocanic acid (cis -UCA), but reactive oxygen species (ROS) also plays an important role. Eicosapentaenoic acid (EPA) can inhibit photocarcinogenesis, but due to its polyunsaturated nature it is susceptible to oxidative damage by ROS. The antioxidant defense system may therefore be challenged upon ultraviolet-B (UVB) irradiation in the presence of EPA. We investigated whether topically applied EPA in mice could protect against local immunosuppression (contact hypersensitivity response to dinitrofluorobenzene) induced by UVB radiation (1.5 J/cm2), or topically applied cis -UCA (150 nmol/cm2) or thymidine dinucleotides (pTpT) (5 nmol/cm2). The influence of EPA on epidermal lipid peroxidation and antioxidant status was also measured. UVB irradiation, cis -UCA and pTpT all caused 70% immunosuppression. Topical pretreatment of mice with EPA partially protected against immunosuppression; the EPA dose needed to accomplish this was 10 nmol/cm2 for UVB irradiation, 100 nmol/cm2 for cis -UCA and 1000 nmol/cm2 for pTpT. Higher EPA doses caused higher UVB-induced lipid peroxidation and lower vitamin C levels. Glutathione only decreased with the highest EPA dose whereas vitamin E was not decreased after UVB irradiation. In conclusion, topically applied EPA protects against UVB-, cis -UCA- and pTpT-induced immunosuppression and maintenance of an adequate antioxidant defense seems to be an important prerequisite for the protective action by EPA. [source] Renal Failure Five Years After Lung Transplantation Due to Polyomavirus BK-Associated NephropathyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010A. Egli Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log10 copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10,29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy. [source] Allotransplantation of Cryopreserved Parathyroid Tissue for Severe Hypocalcemia in a Renal Transplant RecipientAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010S. M. Flechner We report the successful allotransplantation of cryopreserved parathyroid tissue to reverse hypocalcemia in a kidney transplant recipient. A 36-year-old male received a second deceased donor kidney transplant, and 6 weeks later developed severe bilateral leg numbness and weakness, inability to walk, acute pain in the left knee and wrist tetany. His total calcium was 2.6 mg/dL and parathormone level 5 pg/mL (normal 10,60 pg/mL). He underwent allotransplantation of parathyroid tissue cryopreserved for 8 months into his left brachioradialis muscle. Immunosuppression included tacrolimus (target C0 10,12 ng/mL), mycophenolate mofetil and steroids. Within 2 weeks, the left knee pain, leg weakness and numbness resolved, and by 1 month he could walk normally. After a peak at month 2, his parathyroid hormone (PTH) level fell to <10 pg/mL; therefore at month 3 he received a second parathyroid transplant from the same donor. Eight months later (11 months after initial graft) he has a total calcium of 9.3 mg/dL, PTH level 15 pg/mL and is clinically asymptomatic. The amount of parathyroid tissue needed to render a patient normocalcemic is not known. In our case, the need for second transplant suggests that the amount of tissue transferred for an allograft may need to be substantially greater than for an autograft. [source] Islet Transplantation in Type 1 Diabetics Using an Immunosuppressive Protocol Based on the Anti-LFA-1 Antibody EfalizumabAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010A. M. Posselt The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival. [source] | ||||||||||||||||||||||||||||||||||||||||