Reversal of defective lymphoproliferation in postoperative patients with colon cancer

Summary To establish a method for evaluation of immunological parameters in small blood samples, a whole blood technique was developed for the estimation of mitogen- or antigen-induced proliferation. Studies regarding cellular immunity in patients with colon cancer were done with 108 patients in all tumor stages, aged 32 to 80 years. They were studied before surgery and 10 days after operation. A group of 35 patients were further tested 3 months after surgical treatment. In patients with colon cancer the proliferative responses of peripheral blood lymphocytes to mitogens were significantly lower in comparison to healthy controls. These results were found when the response to concanavalin A, phytohemagglutinin, OKT 3, and pokeweed mitogen were analyzed preoperatively and 10 days postoperatively. There was no relation to the stage of disease. The marked reduction of mitogen responses was followed by a gradual return toward normal values 3 months after surgical resection of neoplastic growth in 80% of the patients. Our studies indicate that the defects were largely restored when testing was performed 3 months after operation. Using this result, it will be possible to perform longterm studies in order to establish if there is a correlation between the return to normal immune reactivity and the survival of individual patients.Dedicated to Professor Dr. E. Hecker on the occasion of his 60th birthday     

Postpericardiotomy syndrome during intensive immunosuppression after cardiac transplantation

A 15-year-old man with end-stage heart failure due to dilated cardiomyopathy, underwent heart transplantation. In the second postoperative week, while being treated with monoclonal antibodies (OKT3), cyclosporine and azathioprine, he developed a postpericardiotomy syndrome and cardiac tamponade, which necessitated emergency pericardiocentesis. Corticosteroids, administered according to the immunosuppression protocol, resulted in the prompt subsidence of the syndrome. This is the first report of a large pericardial effusion and cardiac tamponade due to a postpericardiotomy syndrome in an adult cardiac recipient.     

Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia

Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.     

Severe neutropenia in T-large granular lymphocyte leukemia corrected by intensive immunosuppression

 Optimum treatment of severe neutropenia, a major factor for morbidity and mortality in T-large granular lymphocyte (LGL) leukemia, is undefined. We observed a rapid improvement of the neutrophil count in a patient with T-LGL leukemia and severe neutropenia after the combined administration of anti-lymphocyte-globulin (ALG), cyclosporin A, prednisone, and granulocyte colony-stimulating factor (G-CSF). Although G-CSF treatment was terminated after 7 days, the neutrophil count has persisted above 1.0×10⁹/l for up to 6 months now. Oral methotrexate is given continuously as treatment for T-LGL leukemia. The response to this immunosuppressive regimen suggests a T-cell-mediated mechanism as the underlying cause for neutropenia in T-LGL leukemia. Received: 26 January 1996 / Accepted: 3 May 1996     

Efficacy of intensive immunosuppression in exacerbated rheumatoid arthritis-associated interstitial lung disease

Objectives: Acute or subacute exacerbations are recognized as a severe complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Nevertheless, the role of intensive immunosuppression in RA-ILD remains elusive. We attempted to evaluate the clinical characteristics and efficacy of immunosuppressive treatment in exacerbated RA-ILD.

Methods: Clinical data, including respiratory function, imaging, treatment, and prognosis, were retrospectively collected for 17 patients with RA-ILD who required hospitalization at the University of Tokyo Hospital due to an acute exacerbation (12 patients) or subacute exacerbation (5 patients).

Results: Patients with RA-ILD demonstrated a significantly higher titers of anticyclic citrullinated peptide antibodies compared with RA patients in Japanese Ninja registry, suggesting the role of adaptive immunity. Immunosuppressive treatment suppressed the deterioration of pulmonary functions with improved ground grass opacity and consolidation. In particular, in patients with less fibrosis on computed tomography (CT) images showed a better response to treatment. Although five patients treated with combination therapy, including cyclophosphamide, showed a severely decreased lung volume, these intensive therapies provided a good prognosis without fatalities for the average observation period of 474 days.

Conclusions: Immunosuppressive therapy is effective for exacerbations of RA-ILD. For severe cases with low respiratory function, intensive therapy, including cyclophosphamide, has a potential to improve the prognosis.     

Procalcitonin in patients with and without immunosuppression and sepsis

Summary High serum levels of procalcitonin (PCT) are observed in patients with sepsis or severe infection. In a prospective study of 122 hospitalised adult medical patients with sepsis, serum PCT was determined on admission and for 9 days thereafter. Patients with no alteration in their immune system showed high PCT values up to day 5, decreasing to normal levels by day 9. Patients with sepsis and immunodeficiency had high values on days 0 to 2, similar to the first group, but showed significantly lower levels on the following 3 days. PCT concentrations fell to base line levels on days 6 to 9 of the sepsis episode in both groups. The observed difference was not significantly related to the kind of causative microorganism or a culture negative sepsis. Leukopenia seemed to go together with lower PCT values after day 2 of the episode, but this could not be proven statistically.

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Procalcitonin bei Patienten mit Sepsis mit und ohne Immunsuppression

Zusammenfassung Bei Patienten mit Sepsis oder schweren Infektionen sind erhöhte Werte des Hormons Procalcitonin (PCT) beschrieben worden. In einer prospektiven Studie wurde PCT im Serum von 122 erwachsenen Patienten mit Sepsis, die in der Abteilung für Innere Medizin hospitalisiert waren, am Tag der Aufnahme und bis zu 9 Tage danach bestimmt. Patienten mit intaktem Immunsystem hatten bis zum 5. Tag erhöhte PCT-Werte, die sich bis zum 9. Tag normalisierten. Patienten mit Sepsis und Immundefizienz hatten am Tag 0 bis 2 ebenfalls erhöhte Werte. Sie wiesen jedoch an den folgenden 3 Tagen signifikant niedrigere Werte auf als die Patienten der ersten Gruppe. Die PCT-Konzentrationen gingen am Tag 6 bis 9 der Sepsisepisode in beiden Gruppen auf Normalwerte zurück. Der beobachtete Unterschied der PCT-Konzentrationen stand weder in signifikantem Zusammenhang mit der Art des Mikroorganismus, der die Sepsis verursachte, noch mit einer Sepsis mit negativer Blutkultur. Eine Leukopenie scheint mit niedrigeren PCT-Werten am Tag 2 der Sepsisepisode einherzugehen, dies konnte jedoch nicht statistisch bewiesen werden.

     

Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function

Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression.     

Mycobacterial T cell responses in HIV-infected patients with advanced immunosuppression

Antimycobacterial T cell reactivity at different stages of HIV infection was investigated. Subjects were screened with purified protein derivative (PPD), early secreted antigenic target (ESAT)-6, and culture filtrate protein (CFP)-10 antigens for interferon (IFN)-gamma-producing effector T cell responses by direct ex vivo enzyme-linked immunospot (ELISpot) assay. The proportion of responders to PPD tuberculin decreased with a reduction in CD4 T cell count, whereas the proportion of responder to ESAT-6 and CFP-10 did not. The main sources of IFN-gamma secretion were CD4 cells, and the relative responses to ESAT-6 and CFP-10 significantly increased in HIV-infected patients with decreasing CD4 cell count. This may reflect early signs of reactivation, reinfection, or a restricted, inefficient immune response to Mycobacterium tuberculosis.     

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3⁺TCRα/β⁺CD4⁻CD8⁻ “double negative” T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.     

Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration

Objective: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. Methods: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. Results: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p<0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. Conclusions: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.     

Post-transplantation lymphoproliferative disorder in pediatric patient

Immunosuppressive therapy for transplanted patients exposes them to a high risk of developing posttransplantation lymphoproliferative disorders (PTLD). We report the case of a child undergoing heart transplantation at seven months of age who developed PTLD at nine years of age, diagnosed by resection of a pulmonary nodule.     

Post-transplantation outcome in non-alcoholic steatohepatitis cirrhosis: Comparison with alcoholic cirrhosis

Introduction and objectivesNon-alcoholic steatohepatitis (NASH) indication of liver transplant (LT) has increased recently, whereas alcoholic cirrhosis remains a major indication for LT. To characterize NASH-related cases and to compare the post-transplant outcome of these two conditions represents our major objective.Material and methodsPatients undergoing LT for NASH between 1997 and 2016 were retrieved. Those transplanted between 1997 and 2006 were compared to an “age and LT date” matched group of patients transplanted for alcoholic cirrhosis (ratio 1:2). Baseline features and medium-term outcome measures were compared.ResultsOf 1986 LT performed between 1997 and 2016, 40 (2%) were labeled as NASH-related indications. NASH-related cases increased initially (from 0.8% in 1997–2001 to 2.7% in 2002–2006) but remained stable in subsequent years (2.3%). Hepatocellular carcinoma (HCC) prevalence was greater in NASH-vs alcohol-related cirrhosis (40% vs 3%, p = 0.001). The incidence of overweight, obesity, arterial hypertension, dyslipidemia, diabetes, hyperuricemia, renal insufficiency and cardiovascular (CV) disease was similar in both groups at 5 years post-LT. Five-year survival was higher in NASH but without reaching statistical significance (83% vs 72%, p = 0.21). The main cause of mortality in NASH-LT patients was HCC recurrence.ConclusionMost previously considered cryptogenic cases are actually NASH-cirrhosis. While the incidence of this indication is increasing in many countries, it has remained relatively stable in our Unit, the largest LT center in Spain. HCC is common in these patients and represents a main cause of post-transplant mortality. Metabolic complications, CV-related disease and 5-yr survival do not differ in patients transplanted for NASH vs alcohol.     

Response of recurrent giant cell myocarditis in a transplanted heart to intensive immunosuppression

A 35-year-old man developed giant cell myocarditis resulting in severe congestive cardiac failure. He needed urgent orthotopic cardiac transplantation despite maximal doses of inotropes and augmentation with an intra-aortic balloon pump. The patient presented with rhythm disturbances and echocardiographically diminished ventricular function at subsequent follow-up. Biopsies then taken revealed recurrence of myocarditis in the transplanted heart. Investigations revealed no obvious cause for the myocardial granulomas nor any evidence of systemic granulomatous disease. The patient received, in addition to maintenance cyclosporin A and azathioprine, high doses of corticosteroids which resulted in complete resolution of the inflammatory process and no recurrence has been detected to date. This case shows that giant cell myocarditis can recur in the transplanted heart despite routine immunosuppression with azathioprine and cyclosporin A and that additional treatment with high dose corticosteroids is effective in causing regression of the inflammatory process.     

免疫功能低下与老年人肺结核

免疫功能是机体防御性反应，是机体识别并消除外来损害以保持体内环境的平衡和稳定的重要功能。结核病的发生和发展取决于很多因素，其中最重要的是感染的菌量及其毒力的大小和机体的反应性（免疫反应或变态反应）。如果机体的免疫功能低下，感染菌株的毒力较强且数量较多时，将导致结核病的发生和发展；反之机体的免疫功能较好，感染菌株的毒力不强且数量不多时，则导致临床痊愈，感染免疫的建立。结核病的免疫反应以细胞免疫为主，即T细胞起主要作用。成人型及内源性肺结核的发病与否及发病类型与人体的免疫功能关系密切。近年来由于恶性…     

nm23 expression in gastric carcinoma and its relationship with lymphoproliferation

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B-cell lymphoproliferation in chronic inflammatory rheumatic diseases

Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sj?gren's syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.