Early Immunosuppression Research Articles

Early Combined Immunosuppression in Crohn Disease: A Community-Based Trial

In treatment-naive patients with Crohn disease, early treatment with a combination of a tumor necrosis factor (TNF) blocker and an antimetabolite (azathioprine, 6-mercaptopurine, or methotrexate), or early combined immunosuppression (ECI), is recognized to result in the highest remission rates. In an industry-funded, cluster-randomized study of community practices, investigators tested the efficacy of ECI versus conventional step-up management. The primary outcome was the rate of steroid-free remission at month 12. Patients were followed for 24 months. In ECI-randomized practices, after initial mandated steroid trials (4 weeks in …

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial

Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. AbbVie Pharmaceuticals.

Sudden hearing loss and Crohn disease: when Cogan syndrome must be suspected

Cogan’s syndrome is a rare systemic vasculitis of unknown origin. It is characterized by the presence of worsening audiovestibular and ocular symptoms that may manifest simultaneously or sequentially. No specific diagnostic laboratory tests or imaging studies exist. The diagnosis is clinical and should be established as early as possible so as to initiate prompt treatment with steroids and prevent rapid progression to deafness or blindness and potentially fatal systemic involvement. We report a case of association between Cogan’s syndrome and ileal Crohn’s disease which we believe deserves attention since, after an accurate review of the literature, we have found approximately 250 reports of patients with Cogan’s syndrome, only 13 of whom with concurrent chronic inflammatory bowel disease; of these 13 cases, none experienced improvement after therapy. In the light of the good outcome obtained in our case, we proposed a valid treatment option with boluses of steroids, combined with early systemic immunosuppression and intra-tympanic steroid injections.

Reviewing the recommendations for lupus in children.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder with severe morbidity and mortality and diverse systemic involvement. Disease onset occurs during childhood in approximately 15% of patients with SLE. It is important to treat the attacks adequately and prevent further flares for favorable long-term outcomes. The aim of effective disease management with early immunosuppression is to achieve symptomatic resolution and improvement in the quality of life by maintaining sustained remission and thereby preventing tissue damage. Adult literature on SLE management has evolved considerably over the past few decades based on observations from clinical studies investigating different immunosuppressive agents. We lack well-designed randomized controlled trials in children with SLE, thus we mainly depend on adult literature. Here, we review the literature for the current management of SLE in children and we present the recommendations and suggestions with the level of evidence.

Stem cell transplantation as a dynamical system: are clinical outcomes deterministic?

Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning, and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper, parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed.

S9 Acute Inflammatory Presentation Associates With Survival In Interstitial Lung Disease And Extracorporeal Membrane Oxygenation-requiring Severe Respiratory Failure: A Single Centre Case Series

Introduction Patients with interstitial lung disease (ILD) and severe respiratory failure (SRF) requiring mechanical ventilation are widely perceived to have poor outcomes. A therapeutic strategy incorporating extracorporeal membrane oxygenation (ECMO) improves all cause SRF survival. There exist no data on the use of ECMO in severe ILD. ECMO may offer lung rest, reduce the inflammatory burden associated with mechanical ventilation and allow time for effective immunosuppression. We hypothesised that the use of ECMO and early immunosuppression increases survival in patients with ILD in whom mechanical ventilation was failing. Methods Retrospective interrogation of a single centre ECMO database for patients with ILD between 2011 and 2014. Variables collected included diagnosis; immunosuppression regimen; duration of symptoms prior to ECMO initiation; serum biochemistry; clinical severity score (SOFA) and survival to ECMO decannulation, ICU discharge and at 6 months. ECMO centre admission computed tomography (CT) thorax scans were independently analysed for pattern and degree of abnormality by two radiologists. Variables were compared between responders (those who survived without lung transplant) and non responders (composite group of those who died and one patient who survived with lung transplantation). Two-tailed t-tests were used for all comparisons. Results 12 patients with an ILD diagnosis who received ECMO were identified. ECMO and ICU survival was 58.3%. The group of responders had a shorter duration of symptoms prior to ECMO (p = 0.04), a higher CRP (p = 0.046), a higher SOFA score (p = 0.01) and a lower preponderance of diffuse alveolar damage (DAD) on CT (p = 0.19) although there was no difference in overall extent of CT abnormality. (Table 1). Conclusions The use of ECMO and early immunosuppression led to a 58.3% survival in a group of ILD associated SRF who would otherwise have been highly likely to die. The responders were characterised by a more acute and more inflammatory presentation. We suggest that ECMO and immunosuppression should be considered in patients with ILD and SRF who are failing mechanical ventilation.

Prolonged Immunosuppression Preserves Nonsensitization Status After Kidney Transplant Failure

When kidney transplants fail, transplant medications are discontinued to reduce immunosuppression-related risks. However, retransplant candidates are at risk for allosensitization which prolonging immunosuppression may minimize. We hypothesized that for these patients, a prolonged immunosuppression withdrawal after graft failure preserves nonsensitization status (PRA 0%) better than early immunosuppression withdrawal. We retrospectively examined subjects transplanted at a single center between July 1, 1999 and December 1, 2009 with a non-death-related graft loss. Subjects were stratified by timing of immunosuppression withdrawal after graft loss: early (≤3 months) or prolonged (>3 months). Retransplant candidates were eligible for the main study where the primary outcome was nonsensitization at retransplant evaluation. Non-retransplant candidates were included in the safety analysis only. We found 102 subjects with non-death-related graft loss of which 49 were eligible for the main study. Nonsensitization rates at retransplant evaluation were 30% and 66% for the early and prolonged immunosuppression withdrawal groups, respectively (P=0.01). After adjusting for cofactors such as blood transfusion and allograft nephrectomy, prolonged immunosuppression withdrawal remained significantly associated with nonsensitization (adjusted odds ratio=5.78, 95% CI [1.37-24.44]). No adverse safety signals were seen in the prolonged immunosuppression withdrawal group compared to the early immunosuppression withdrawal group. These results suggest that prolonged immunosuppression may be a safe strategy to minimize sensitization in retransplant candidates and provide the basis for larger or prospective studies for further verification.

Clinical Analysis of 10 Years Protocol Biopsy After Kidney Transplantation.

Purpose. The steady advances in immunosuppression have enabled control of early acute rejection, but long-term graft survival remains unchanged. Chronic histopathological changes influence graft survival rate. The aim of this study was to establish the relationship of risk factors interstitial fibrosis and tubular atrophy (IF/TA) on 10 years protocol biopsy.Methods. We assessed the histological findings obtained at 10 years protocol biopsy after living-donor kidney transplantation(KTx) of 62 patients who received kidney allografts between 1986 and 2003. Using the Banff'07 classification, we classified the patients into two groups, Group1 was less than IF/TA GradeI, Group2 was more than IF/TA GradeII. Risk factors for IF/TA were analyzed retrospectively.Results. The mean age of the recipient was 9.96±5.29 years old, 10 patients (16%) had a kidney from ABO incompatible donor. 62 patients were classified Group1 (n=36) and Group2 (n=26), there were no significant difference in original disease, recipient's age and sex, HLA mismatch, the relation of donor to recipient, CNI, CIT (Cold ischemic time) and except donor's age (38.8±6.97 years old (Group1) vs. 42.6±7.29 years old (Group2), p<0.05). But no significant difference, rate of ABO incompatible kidney transplantation (ABO-iKTx) had more Group1 than Group2 (22%(Group1) vs. 7.6%(Group2), NS). There were no significant difference evaluation of acute rejection(AR) within 1 years KTx between both Groups. We observed AR at 1 and 5 years protocol biopsy after KTx, Evaluation of AR were 22% and 8.5% of Group1, 24% and 28% of Group2. The ratio more than IF/TA GradeII were 20% in Group1 and 44% in Group2(p<0.05). eGFR post-transplantation was significantly difference between both groups (58.6±14.1(Group1) vs. 48.9±17.9(Group2)ml/min at 10 years, p<0.05).Conclusion. Chronic histopathological graft injury were established at 5 years KTx. IF/TA Grade of ABO-iKTx tend to be low, we should study that early modification of early immunosuppression may prevent the chronic histopathological graft injury and alter the long-term graft outcome.

SAT0294 Longitudinal Analysis Suggests Clinical Outcomes in Takayasu Arteritis Are Improved by Early Combination Immunosuppression with Serial Non-Invasive Imaging

BackgroundTakayasu arteritis (TA), a granulomatous large vessel vasculitis affecting young patients, pre-disposes to stenoses and aneurysmal dilatation of the aorta and its branches. Despite morbidity remaining high, evidence for the...

1053 Early Combined Immunosuppression for the Management of Crohn's Disease: A Community-Based Cluster Randomized Trial

1053 Early Combined Immunosuppression for the Management of Crohn's Disease: A Community-Based Cluster Randomized Trial

OP003 Circadian clock function maintains mucosal architecture and protects against intestinal inflammation in mice

Background: In the last years, the interest of circadian rhythms as regulators of intestinal inflammation has increased substantially. Consisting of a range of clock genes including Per1 and Per2, the molecular clock machinery is thought to be engaged in modulating intestinal barrier function and gut homeostasis, features which are highly disturbed in inflammatory bowel disease (IBD). Elucidating the precise role of clock genes in the intestine may therefore highlight new pathophysiological mechanisms and new therapeutic approaches. Methods: Here, we used Per1/Per2 mutant mice and wildtype controls to investigate the functional consequence of circadian disruption on gastrointestinal tract morphology and intestinal inflammation. Small and large intestines were evaluated histologically at basal conditions. Experimental chronic colitis was induced by cyclic administration of 2% dextran sulphate sodium (DSS) in the drinking water, and colitis severity was determined by mouse endoscopy and clinical scores (murine endoscopic index of colitis severity, disease activity index). Biopsies were taken and further investigated via RT-PCR, western blotting and immunofluorescence staining. Results: At baseline, Per1/2 mice displayed mucosal alterations in the small and large intestines, characterized by a diminished crypt length-to-width ratio and reduced numbers of goblet and Paneth cells. Strikingly, mutant mice exhibited severely increased clinical symptoms of colitis (e.g. body weight loss, rectal bleeding, and diarrhea) and gross lethality in response to DSS. BrdU labeling revealed increased numbers of proliferative intestinal epithelial cells (IEC) in Per1/2 mice, but a restricted migratory capacity along the crypt axis. Analyzing the fate of individual IEC, we detected elevated protein level of RIP3, a marker of necroptotic cell death, in IEC at the crypt base, indicating that aberrant cell death in the proliferative region of intestinal crypts is responsible for the observed morphological changes in Per1/2 mice. Together, these data suggest that Per1/Per2 deficiency modulates cell death events, and thus influences intestinal homeostasis. Conclusions: Our data render intact circadian rhythm crucially important for intestinal barrier function and maintenance. Thus, therapeutic interventions stabilizing circadian rhythm may be promising options for the treatment of IBD. OP004 Early combined immunosuppression for the management of Crohn’s disease: A community-based cluster randomized trial R. Khanna1, B.G. Levesque1,2, B. Bressler3, G. Zou1,4, L. Stitt1, G.R. Greenberg5, R. Panaccione6, A. Bitton7, P. Pare8, S. Vermeire9, G. D’Haens1,10, D. MacIntosh11, W.J. Sandborn1,2, M.K. Vandervoort1, J.C. Morris1, B.G. Feagan1,12 *. 1Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London, Ontario, Canada, 2University of California, San Diego, Division of Gastroenterology, La Jolla, United States, 3St. Paul’s Hospital, Department of Gastroenterology, Vancouver, British Columbia, Canada, 4Western University, Department of Epidemiology and Biostatistics, London Ontario, Canada, 5Mount Sinai Hospital, Division of Gastroenterology, Toronto Ontario, Canada, 6University of Calgary, Division of Gastroenterology & Hepatology, Calgary Alberta, Canada, 7McGill University, Division of Gastroenterology, Montreal Quebec, Canada, 8Laval University, Hopital du St-Sacrement, Quebec City, Quebec, Canada, 9Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 10University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 11Dalhousie University, Division of Gastroenterology, Halifax, Canada, 12Western University, Department of Epidemiology and Biostatistics, Department of Medicine, London Ontario, Canada

OP004 Early combined immunosuppression for the management of Crohn's disease: A community-based cluster randomized trial

s of the 9th Congress of ECCO the European Crohn’s and Colitis Organisation S3 Results: Twenty-one centers (1084 patients) were assigned to ECI and 18 (898 patients) to CM. The mean age of the patients was 44.2 in the ECI group and 44.1 in the CM group. Mean HBS scores were 4.1 in both groups. The proportion of patients in the ECI and CM groups who received combination of antimetabolite/TNF-antagonist by 12 months was 15.1% and 6.5% P< 0.001) and 19.7% and 9.6% by 24 months (P< 0.001). Mean % (SD) remission rates in the ECI and CM groups were 66 (14) and 62 (17) at 12 months (P= 0.65) and 73 (8) and 65 (17) at 24 months (P= 0.35). However, highly significant and clinically important differences in the rates of complications, surgeries, and the combined outcome of hospitalizations, complications, and surgeries were observed in favor of ECI over 24 months (Figure 2). The 24 month actuarial estimates for the combined outcome were 27.7% and 35.1% in the ECI and CM groups, respectively (hazard ratio adjusted for CD caseload and country: 0.74 [0.62, 0.87, P< 0.001]). Figure 2. Hospitalizations, complications*, and surgeries for patients in the ECI and CM groups over 24 months. *Abscess, new fistula, extra-intestinal manifestations of CD and serious AEs. Conclusions: Community-based data indicate that (1) a symptom based conventional approach to CD management may not be optimal and (2) ECI may be more effective in preventing CD-related complications. OP005 Is elderly-onset ulcerative colitis a different entity? Natural disease course and treatment response compared to adult-onset disease in the population-based IBD-SL cohort S. Jeuring1,2 *, T. Van den Heuvel1,2, M. Zeegers3,4, W. Hameeteman1, M. Romberg-Camps5, L. Oostenbrug6, A. Masclee1,2, D. Jonkers1,2, M. Pierik1,2. 1Maastricht University Medical Center+, Internal Medicine Division Gastroenterology-Hepatology, Maastricht, Netherlands, 2Maastricht University Medical Center+, NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht, Netherlands, 3University of Birmingham, Epidemiology and Public Health, Birmingham, United Kingdom, 4Maastricht University Medical Center+, Complex Genetics, Cluster of Genetics and Cell Biology, Maastricht, Netherlands, 5ORBIS Medical Centre, Gastroenterology and Hepatology, Sittard, Netherlands, 6Atrium Medical Center, Internal Medicine and Gastroenterology, Heerlen, Netherlands Background: Population ageing is a worldwide demographic phenomenon. Since the incidence of ulcerative colitis (UC) is increasing, elderly-onset UC will become more prevalent in the near future. It is unclear whether elderly-onset UC is a different phenotypic subgroup, requiring different treatment strategies. Information on disease course and treatment response of elderly-onset UC patients is scarce and conflicting, and often derived from small, selected UC populations. Therefore, we aimed to compare disease course and treatment response between adultand elderly-onset UC in our population-based

Protocol Based Induction Therapy Improves Rejection Rates, Complications, and Transplant Event Costs in Adult Kidney Transplant Recipients

Induction therapy is the cornerstone of early immunosuppression in kidney transplant recipients. However, the choice of induction agent based on donor and recipient characteristics is controversial. A number of transplant programs utilize the same induction agent in all patients; while other programs utilize a risk/benefit approach, prescribing less potent therapy in low immunologic risk patients and reserving potent induction therapy for high immunologic risk recipients. There are no studies comparing these approaches.

Combined bilateral retinal arteriolar and retinal vein occlusion: An unusual presentation of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a rare autoimmune disease associated with multi-organ damage mediated by tissue-binding autoantibodies and immune complexes. [1] Common ocular manifestations of SLE include nonspecific conjunctivitis, anterior uveitis, or iridocyclitis, which rarely threaten vision. In contrast, retinal vasculitis and optic neuritis are serious manifestations. [2] Branch retinal arteriolar occlusion (BRAO) and branch retinal vein occlusion (BRVO) in patients younger than 30 years of age is rarely caused by atheromatous diseases. Other diverse etiologies are more likely to be inflammatory and infectious conditions. Here, we have report a case of a 17-year-old woman with SLE and hypocomplementenemia, who presented with sudden loss of vision. A rare presentation of SLE is found as combined BRAO and BRVO in both the eyes (OU). Despite advances in the understanding of pathophysiology of SLE, its complications remains enigmatic and, in some instances, it may be multifactorial. Early accurate diagnosis and aggressive immunosuppression is recommended, which helps in the management and preservation of the vision.

Panresistant Cytomegalovirus in a Kidney Transplant Recipient

Cytomegalovirus (CMV) is an important pathogen often encountered after solid organ transplantation and is associated with increased morbidity and mortality. Resistance of CMV to antiviral agents is becoming more common but with few treatment strategies. Two specific mutations in the CMV genome--the UL97 and UL54 genes--correlate with antiviral drug resistance. We describe a 49-year-old, CMV-seronegative woman who received a CMV-seropositive donor kidney transplant and appropriate CMV prophylaxis. Approximately 1 month after transplantation, the patient developed CMV viremia that responded to valganciclovir. She was later diagnosed with recurrent CMV infection, CMV resistance, and both the UL97 and UL54 gene mutations. The patient responded to foscarnet and significant reduction of immunosuppression; she was negative for CMV viremia for the next 12 months. This case illustrates the importance of having heightened awareness for the possibility of panresistant CMV early and decreasing immunosuppression as the cornerstone of treatment.

Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study

Mitoxantrone (MTX) is an antineoplastic agent that can induce hepato- and haematotoxicity. This work aimed to investigate the occurrence of cumulative early and late MTX-induced hepatic and haematological disturbances in an vivo model. A control group and two groups treated with three cycles of 2.5mg/kg MTX at days 0, 10 and 20 were formed. One of the treated groups suffered euthanasia on day 22 (MTX22) to evaluate early MTX toxic effects, while the other suffered euthanasia on day 48 (MTX48), to allow the evaluation of MTX late effects. An early immunosuppression with a drop in the IgG levels was observed, causing a slight decrease in the plasma total protein content. The early bone marrow depression was followed by signs of recovery in MTX48. The genotoxic potential of MTX was demonstrated by the presence of several micronuclei in MTX22 leucocytes. Increases in plasma iron and cholesterol levels in the MTX22 rats were observed, while in both groups increases in the unconjugated bilirubin, C4 complement, and decreases in the triglycerides, alanine aminotransferase, alkaline phosphatase and transferrin were found in plasma samples. On MTX 48, the liver histology showed more hepatotoxic signs, the hepatic levels of reduced and oxidized glutathione were increased, and ATP hepatic levels were decreased. However, the hepatic total protein levels were decreased only in the livers of MTX22 group. Results demonstrated the MTX genotoxic effects, haemato- and direct hepatotoxicity. While the haematological toxicity is ameliorated with time, the same was not observed in the hepatic injury.

Methotrexate: Should We Start Using it in Clinical Practice?

Therapeutic approaches in inflammatory bowel disease have changed significantly in the past decade. Early aggressive immunosuppression has become the mainstay of therapy for patients at risk for complicated disease. Azathioprine is the most widely used immunosuppressant; however, a subgroup of patients is intolerant or refractory. Since the late 1990s, methotrexate (MTX) has become more widely used as an immunomodulator in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. Yet according to recent clinical data, methotrexate remained the second most commonly used immunosuppressive in inflammatory bowel diseases. Two landmark trials and subsequent studies provided evidence for the use of methotrexate in Crohn's disease, both for induction and maintenance of remission. The evidence is less solid in ulcerative colitis, for which results of further randomized controlled trials are pending (e.g. Meteor, Merit). A potential new indication of MTX could be combination therapy with biologicals. While this is state of the art therapy in rheumatoid arthritis, data in inflammatory bowel diseases are less clear. Some studies suggest that combination with immunosuppressants could prevent the development of anti-drug antibodies, while others suggested anti- TNF induced autoimmune disorders as a potential indication. In contrast, improved efficacy was not reported by one study (COMMIT). Limitations include frequent side effects, route of administration, pregnancy and concerns about long-term safety. This review summarizes current knowledge on the efficacy and side effects of methotrexate, and tries to reevaluate the drug in the current IBD armamentarium.

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyperresponsiveness, Th2-inflammation, Muc5ac expression, eosinophilia, and HDM-specific Ig compared to HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was two-fold higher in CDPM+HDM mice compared to HDM-mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and Tregs, resulting in suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific-antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.

Expansion of Memory-Type CD8+ T Cells Correlates With the Failure of Early Immunosuppression Withdrawal After Cadaver Liver Transplantation Using High-Dose ATG Induction and Rapamycin

We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vβ/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

When Should High-Grade Heart Block Trigger a Search for a Treatable Cardiomyopathy?

High-degree heart block is an uncommon manifestation of acute myocarditis in adults. The rate of heart block requiring a pacemaker in biopsy-proven acute lymphocytic myocarditis generally is low but has been reported in up to 8.3% of cases.1 Important exceptions include cardiac sarcoidosis and giant cell myocarditis (GCM), 2 uncommon and idiopathic disorders for which early immunosuppression may improve clinical outcomes. High-degree heart block occurs in the course of biopsy-proven cardiac sarcoidosis in 23% to 30% of cases (Table).2 In GCM, second- or third-degree heart block requiring a pacemaker occurs in 25% of cases.3 View this table: Table. Prevalence of Various Cardiac Findings in Cardiac Sarcoidosis During the Course of Disease Article see p 303 This relatively high rate of heart block reflects the severity of the clinical course of cardiac sarcoidosis and GCM, which have a higher rate of death and heart transplantation than lymphocytic myocarditis.1,4 Unlike acute lymphocytic myocarditis, for which immunosuppression usually is not beneficial,5 GCM or cardiac sarcoidosis may improve with certain combinations of immunosuppressive drugs. In the case of acute GCM, cyclosporine combined with corticosteroids and usually a T-cell lytic agent like muromonab-CD3 improves transplant-free survival.6 Uncontrolled case series also suggested that left ventricular (LV) dysfunction due to cardiac sarcoidosis may improve with corticosteroid therapy.7 Because GCM and cardiac sarcoidosis are rare disorders, endomyocardial biopsy is not routinely recommended to detect them in the setting of complete heart block unless cardiomyopathy is present.8 Although a recommendation class was not assigned to …