Identificazione di profili di rischio cardiovascolare nel trapianto di rene: polimorfismi di geni coinvolti nei processi di infiammazione e di apoptosi

Introduction. Cardiovascular disease (CVD) represents the main cause of morbidity and mortality in kidney recipients. This study was undertaken to assess the impact of functional polymorphisms located in cytokine and apoptosis genes on CVD after kidney transplantation. Cytokine polymorphisms, generally located in gene regulatory regions, are associated with high and low cytokine production and are likely to modulate the magnitude of inflammatory responses following transplantation, depending on the balance between the levels of pro-inflammatory and antiinflammatory cytokines. The role of apoptosis in atherosclerosis has not been completely elucidated, and here we explored the hypothesis that the heterogeneity in cardiovascular risk in kidney recipients may also be linked to functional polymorphisms involved in apoptosis induction. Purpose. In the search for relevant genetic markers of predisposition to CVD after renal transplant, the present investigation was undertaken to identify the clinical impact of polymorphisms of cytokines TNF-α, TGF-β, IL-10, IL-6, IFN-γ and IL-8 and of apoptosis genes Fas and Caspase 9 in a population of kidney transplant recipients. Materials and methods. The study involved 167 patients who received cadaveric kidney transplantation at our centre between 1997 and 2005 (minimum follow-up of 12 months); 35 of them had experienced cardiovascular events (CVD group) and 132 had no cardiovascular complications (non-CVD group). Genotyping was performed using RFLP (Restriction Fragment Length Polymorphism) for RFLP per IL-8/T-251A, Fas/G-670A e Casp9/R221Q polymorphism and SSP (Sequence Specific Primer) for TNF-α/G-308A, TGF-β/L10P, TGF-β/R25P, IL-10/G-1082A, IL- 10/C-819T, IL-10/C-592A, IL-6/G-174C, IFN-γ/T+874A polymorphisms.Results. We found a significant difference in TNF-α and IL-10 genotype frequencies between the patients who had suffered cardiovascular events and those with no CVD history. The high producer genotype for proflogistic cytokine TNF-α appeared to have a significantly superior prevalence in the CVD group compared to the non-CVD group (40.0% vs 21.2%) and it resulted in a 2.4-fold increased cardiovascular risk (OR=2.361; p=0.0289). On the other hand, the high producer genotype for the antiinflammatory cytokine IL-10 was found in 2.8% of the CVD group and in 16.7% of non-CVD group; logistic regression showed a 0.3-fold reduced risk of CVD associated with genetically determined high IL-10 production (OR=0.278; p<0.0001). The other polymorphisms did not prove to have any impact on CVD. Conclusions. TNF-α and IL-10 gene polymorphisms might represent cardiovascular risk markers in renal transplant recipients.

Liver transplantation for transthyretin amyloidosis: experience of a single center in Italy

Liver transplantation is the only definitive treatment for transthyretin amyloidosis, with an excellent 5-year survival in endemic countries where the Met30 mutation is predominant. We report our experience of liver transplantation for transthyretin amyloidosis. We reviewed the clinical records of 17 transplanted patients (11 males, 6 females; age at liver transplant: 45.7±11.7 years). We had a wide spectrum of non-Met30 mutations (52.9%), with a predominance of Gln89 (23.5%). Five-year survival after transplantation was 43.8%; at multivariate analysis, both non-Met30 mutations (HR 17.3, 95% CI 1.03-291.7) and modified BMI (HR 0.50, 95% CI 0.29-0.87) showed significant and independent prognostic roles (P=0.048 and P=0.015, respectively). Five out of the 9 non-Met30 carriers received combined heart transplantation because of severe cardiomyopathy; they showed a trend towards a better prognosis vs. the 4 patients who did not receive combined heart transplantation (although not statistically significant; P=0.095). At follow-up, no significant improvement of transthyretin amyloidosis manifestations was observed. The results of liver transplantation for transthyretin amyloidosis in our population are poorer than those reported in the literature probably because of the high prevalence of non-Met30 mutations.

Profilo molecolare dei linfomi post-trapianto

Fifty-two cases of monomorphic post-transplant lymphoproliferative disorders (M-PTLD), developed in patients undergone solid organ or bone marrow transplantation, were studied by the application of the tissue micro-array (TMA) technology. They included 50 cases of diffuse large B-cell lymphomas (DLBCL) and 2 Burkitt lymphomas (BL). In order to evaluate the immune-profile a large panel of antibodies was applied including several new markers (Cyclin D2, Cyclin D3, p27, PKC-β, FOXP-1 and Survivin) identified as negative prognostic factors in DLBCL of the immunocompetent patient. Out of 50 DLBCL, 23 cases (46%) had an Activated B Cell (ABC) phenotype, 8 (16%) a Germinal Centre B-cell (GCB) phenotype, and 11 (22%) an Unclassified (UC) phenotype. In 8 cases (16%) the subtype was not demonstrable due to sub-optimal preservation or loss of the tissue core. FISH analysis detected BCL2 gene amplification and MYC rearrangement. EBV was identified in 32 cases (64%) performing immunohistochemistry (LMP-1) and in situ hybridization (EBER). Clinical data and follow-up were available in all cases of malignant lymphomas but one. Thirty-two patients died for progression of disease or complications related to transplant (bleeding, bacterial infections, and multi-organ failure); 17 patients are actually alive and disease-free. M-PTLD are aggressive lymphomas characterized by very poor outcome. The neoplastic process is stimulated by a prolonged immunosuppressive status which is capable to induce alterations of the immune system and allow EBV reactivation in previously infected patients. Indeed EBV infection seems to be the most significant risk factor to predict the development of a PTLD while age, sex, site of involvement and type of transplant do not have significant correlation. Furthermore DLBCL arisen in a setting of immunodeficiency share phenotypic and molecular features with DLBCL of the immunocompetent patient. In particular, the former shows a high incidence of BCL2 gene amplification and this aberration typically correlates with “non-GCB” phenotype. Also M-PTLD do express prognostic markers (PKC-β, cyclin D2, FOXP-1, and Survivin): notably, in our study, PKC-β and FOXP-1 were frequently expressed and they were predictive of a shorter overall survival even in lymphomas recognized to have a good prognosis (GCB-type). Given the fact that such molecules are detectable at the time of the diagnosis, we postulate whether a “tailored” or more specific therapy might be applied in the management of the immune-compromised patient.

Role of SP-A gene polymorphism in lung transplantation

Lung transplantation is a widely accepted therapeutic option for end stage lung disease. Clinical outcome is yet challenged by primary graft failure responsible for the majority of the early mortality, by chronic allograft dysfunction and chronic rejection accounting for more than 30% of deaths after the third postoperative year. Pulmonary surfactant proteins (SP) A, B, C and D are one of the first host defense mechanisms the lung can mount. SP-A in particular, produced by the type II pneumocytes, is active in the innate and adaptive immune system being an opsonin, but also regulating the macrophage and lymphocyte response. The main hypothesis for this project is that pulmonary surfactant protein A polymorphism may determine the early and long term lung allograft survival. Of note SP-A biologic activity seems to be genetically determined and SP-A polymorphisms have been associated to various lung disease. The two SP-A genes SP-A1 and SP-A2 have several polymorphisms within the coding region, SP-A1 (6A, 6A2-20), and SP-A2(1A, 1A0-13). The SP-A gene expression is regulated by cAMP, TTF-1 and glucocorticoids. In vitro studies have indicated that SP-A1 and SP-A2 gene variants may have a variable response to glucocorticoids. We proposed to determine if SP-A gene polymorphism predicts primary graft dysfunction and/or chronic lung allograft dysfunction and if SP-A may serve as a biomarker of lung allograft dysfunction. We also proposed to study the interaction between immunosuppressive drugs and SP-A expression and determine whether this is dependent on SP-A polymorphisms. This study will generate novel information improving our understanding of lung allograft dysfunction. It is conceivable that the information will stimulate the interest for a multi centre study to investigate if SP-A polymorphism may be integrated in the donor lung selection criteria and/or to implement post transplant tailored immunosuppression.

Influenza del sistema immunogenetico KIR nell'alloreattività Natural Killer nel trapianto di rene

Kidney transplantation is the best treatment option for the restoration of excretory and endocrine kidney function in patients with end-stage renal disease. The success of the transplant is linked to the genetic compatibility between donor and recipient, and upon progress in surgery and immunosuppressive therapy. Numerous studies have established the importance of innate immunity in transplantation tolerance, in particular natural killer (NK) cells represent a population of cells involved in defense against infectious agents and tumor cells. NK cells express on their surface the Killer-cell Immunoglobulin-like Receptors (KIR) which, by recognizing and binding to MHC class I antigens, prevent the killing of autologous cells. In solid organ transplantation context, and in particular the kidney, recent studies show some correlation between the incompatibility KIR / HLA and outcome of transplantation so as to represent an interesting perspective, especially as regards setting of immunosuppressive therapy. The purpose of this study was therefore to assess whether the incompatibility between recipient KIR receptors and HLA class I ligands of the donor could be a useful predictor in order to improve the survival of the transplanted kidney and also to select patients who might benefit of a reduced regimen. One hundred and thirteen renal transplant patients from 1999 to 2005 were enrolled. Genomic DNA was extracted for each of them and their donors and genotyping of HLA A, B, C and 14 KIR genes was carried out. Data analysis was conducted on two case-control studies: one aimed at assessing the outcome of acute rejection and the other to assess the long term transplant outcome. The results showed that two genes, KIR2DS1 and KIR3DS1, are associated with the development of acute rejection (p = 0.02 and p = 0.05, respectively). The presence of the KIR2DS3 gene is associated with a better performance of serum creatinine and glomerular filtration rate (MDRD) over time (4 and 5 years after transplantation, p <0.05), while in the presence of ligand, the serum creatinine and MDRD trend seems to get worse in the long term. The analysis performed on the population, according to whether there was deterioration of renal function or not in the long term, showed that the absence of the KIR2DL1 gene is strongly associated with an increase of 20% of the creatinine value at 5 years, with a relative risk to having a greater creatinine level than the median 5-year equal to 2.7 95% (95% CI: 1.7788 - 2.6631). Finally, the presence of a kidney resulting negative for HLA-A3 / A11, compared to a positive result, in patients with KIR3DL2, showed a relative risk of having a serum creatinine above the median at 5 years after transplantation of 0.6609 (95% CI: 0.4529 -0.9643), suggesting a protective effect given to the absence of this ligand.

Timing per l'inserimento in lista dei pazienti affetti da fibrosi cistica che necessitano di trapianto polmonare: casistica di un centro regionale di riferimento

Timing of waiting list entrance for patients with cystic fibrosis in need of pulmonary transplant: the experience of a regional referral centre Objective: Evaluation of parameters that can predict a rapid decay of general conditions of patients affected by Cystic Fibrosis (CF) with no specific criteria to be candidate to pulmonary transplant. Material and methods: Fifteen patients with CF who died for complications and 8 who underwent lung transplantation in the 2000-2010 decade, were enrolled. Clinical data 2 years before the event (body max index, FEV1%, number of EV antibiotic treatments per year, colonization with Methicillin-resistant Staphylococcus aureus (MRSA), pseudomonas aeruginosa mucosus, burkholderia cepacia, pulmonary allergic aspergilosis) were compared among the 2 groups. Results: Mean FEV1% was significantly higher and mean number of antibiotic treatment was lower in deceased than in the transplanted patients (p<0.002 and p<0.001 respectively). Although in patients who died there were no including criteria to enter the transplant list 2 years before the exitus, suggestive findings such as low BMI (17.3), high incidence of hepatic pathology (33.3%), diabetes (50%), and infections with MRSA infection (25%), Pseudomonas aeruginosa (83.3%) and burkholderia cepacia (8.3%) were found with no statistical difference with transplanted patients, suggesting those patients were at risk of severe prognosis. In patients who died, females were double than males. Conclusion: While evaluating patients with CF, negative prognostic factors such as the ones investigated in this study, should be considered to select individuals with high mortality risk who need stricter therapeutical approach and follow up. Inclusion of those patients in the transplant waiting list should be taken into account.

Alterazioni del metabolismo osseo e fratture vertebrali dopo trapianto di rene

Introduction:Persistent Hyperparathyroidism after transplantation (HPT),bone disease and vertebral fractures are an important clinical problem in renal transplant patients. Several factors such as renal osteodystrophy, immunosuppressive therapy, deficit/insufficiency Vitamin D may contribute to that.In literature are described different percentages of HPT, vertebral fractures and Osteoporosis/Osteopenia that may be due to the different therapy and to the different employ of steroid. We analyzed 90 patients who received a renal graft between 2005 e 2010. Patients and Methods: 44 male and 46 female. Average age 52,2± 10,1 years, follow-up 31,3±16,6 months, time on dialysis 37±29,6 months. Patients who had creatinine level greater than 2,5 mg/dl were excluded. Immunosuppressive therapy was based on basiliximab, steroids (1.6 to 2 mg/kg/day progressively reduced to 5 mg/day after 45 days from the transplantation) in all patients + calcineurin inhibitor+ mycophenolate mophetil/mycophenolic acid in 88,8% of patients or Everolimus± calcineurin inhibitor in the others. Patients were studied with X-ray of the spine, dual-energy-X-ray, PTH, 25(OH)VitD. Results: 41,1% had HPT; 41,1% had osteopenia at femoral neck and 36,7% at vertebral column; 16,7% had osteoporosis at femoral neck and 15,6% at vertebral column. 10 patients (11%) had vertebral fractures. Patients with normal bone mineral density, compared to those with osteoporosis/osteopenia, are more younger (average age 46,4±11,7 years vs 54.3±8,6); they have spent less time on dialysis (26,5±14,8 months vs 40,7±32,6) and they have values of 25(OH)VitD higher (22,1±7,6 ng/ml vs 17,8±8,5). Patients with vertebral fractures have values of 25(OH)VitD lowest (14,1±6,4 ng/ml vs 19,7±8,5) and they had transplant since more time (29,1±16,2 vs 48,1±8,7 months). There is a significant correlation between HPT and PTH pre transplantation; HPT and levels of VitD (p<0,05) Conclusion: Prevention of Bone disease and vertebral fractures after renal transplant includes: a)treatment before transplantation b)supplementation of vitamin D with cholecalciferol or calcidiol c)shorten the dialysis time.

Efficacia e sicurezza della profilassi anti-citomegalovirus rispetto alla strategia pre-sintomatica con valganciclovir in pazienti con trapianto di cuore trattati con everolimus o micofenolato

Il CMV è l’agente patogeno più frequente dopo trapianto (Tx) di cuore determinando sia sindromi cliniche organo specifiche sia un danno immunomediato che può determinare rigetto acuto o malattia coronarica cronica (CAV). I farmaci antivirali in profilassi appaiono superiori all’approccio pre-sintomatico nel ridurre gli eventi da CMV, ma l’effetto anti-CMV dell’everolimus (EVE) in aggiunta alla profilassi antivirale non è stato ancora analizzato. SCOPO DELLO STUDIO: analizzare l’interazione tra le strategie di profilassi antivirale e l’uso di EVE o MMF nell’incidenza di eventi CMV correlati (infezione, necessità di trattamento, malattia/sindrome) nel Tx cardiaco. MATERIALI E METODI: sono stati inclusi pazienti sottoposti a Tx cardiaco e trattati con EVE o MMF e trattamento antivirale di profilassi o pre-sintomatico. L’infezione da CMV è stata monitorata con antigenemia pp65 e PCR DNA. La malattia/sindrome da CMV è stato considerato l’endpoint principale. RISULTATI: 193 pazienti (di cui 10% D+/R-) sono stati inclusi nello studio (42 in EVE e 149 in MMF). Nel complesso, l’infezione da CMV (45% vs. 79%), la necessità di trattamento antivirale (20% vs. 53%), e la malattia/sindrome da CMV (2% vs. 15%) sono risultati significativamente più bassi nel gruppo EVE che nel gruppo MMF (tutte le P<0.01). La profilassi è più efficace nel prevenire tutti gli outcomes rispetto alla strategia pre-sintomatica nei pazienti in MMF (P 0.03), ma non nei pazienti in EVE. In particolare, i pazienti in EVE e strategia pre-sintomatica hanno meno infezioni da CMV (48 vs 70%; P=0.05), e meno malattia/sindrome da CMV (0 vs. 8%; P=0.05) rispetto ai pazienti in MMF e profilassi. CONCLUSIONI: EVE riduce significamene gli eventi correlati al CMV rispetto al MMF. Il beneficio della profilassi risulta conservato solo nei pazienti trattati con MMF mentre l’EVE sembra fornire un ulteriore protezione nel ridurre gli eventi da CMV senza necessità di un estensivo trattamento antivirale.

Impatto della glomerulopatia cronica da trapianto sulla disfunzione tardiva del rene trapiantato

INTRODUCTION. Late chronic allograft disfunction (CAD) is one of the more concerning issues in the management of patients (pts) with renal transplant (tx). Humoral immune response seems to play an important role in CAD pathogenesis. AIM OF THE STUDY. To identify the causes of late chronic allograft disfunction. METHODS. This study (march 2004-august 2011) enrolled pts who underwent renal biopsy (BR) because of CAD (increase of creatininemia (s-Cr) >30% and/or proteinuria >1g/day at least one year after tx). BR were classified according to 1997/2005 Banff classification. Histological evaluation of C4d (positive if >25%), glomerulitis, tubulitis, intimal arteritis, atrophy/fibrosis and arteriolar-hyalinosis were performed. Ab anti-HLA research at BR was an inclusion criteria. Pts were divided into two groups: with or without transplant glomerulopathy (CTG). RESULTS. Evaluated BR: 93/109. BR indication: impaired s-Cr (52/93), proteinuria (23/93), both (18/93). Time Tx-BR: 7.4±6.3 yrs; s-Cr at BR: 2.7±1.4 mg/dl. CTG group(n=49) not-CTG group(n=44) p Time tx-BR (yrs) 9.3±6.7 5.3±5.2 0.002 Follow-up post-BR (yrs) 2.7±1.8 4.1±1.4 0.0001 s-Cr at BR (mg/dl) 2.9±1.3 2.4±1.5 NS Rate (%) of pts: Proteinuria at BR 61% 25% 0.0004 C4d+ 84% 25% <0.0001 Ab anti-HLA+ 71% 30% 0.0001 C4d+ and/or Ab antiHLA 92% 43% 0.0001 Glomerulitis 76% 16% <0.0001 Tubulitis 6% 32% 0.0014 Intimal arteritis 18% 0% 0.002 Arteriolar hyalinosis 65% 50% NS Atrophy/fibrosis 80% 77% NS Graft survival 45% 86% 0.00005 Histological Diagnosis: CTG group (n=49:Chronic rejection 94%;IgA recurrence + humoral activity 4%;IIA acute rejection + humoral activity 2%. Not-CTG group (n=44: GN recurrence 27%;IF/TA 23%; acute rejection 23%;BKV nephritis 9%; mild not specific alterations 18%. CONCLUSIONS: CTG is the morphological lesion mainly related to CAD. In the 92% of the cases it is associated with markers of immunological activity. It causes graft failure within five years after diagnosis in 55% of pts.

Studio dei polimorfismi genici degli antigeni minori di istocompatibilità e GvHD/GvL nel trapianto allogenico di cellule staminali emopoietiche

L'outcome dei pazienti sottoposti a trapianto allogenico di cellule staminali emopoietiche è fortemente influenzato da graft versus leukemia (GvL) e graft versus host disease (GvHD) che sono mediate, almeno in parte, dagli antigeni minori di istocompatibilità (mHAgs). In letteratura sono stati identificati 26 mHAgs che sono stati correlati a GvHD/GvL con risultati incompleti e in alcuni casi contrastanti; inoltre manca una metodica che sia in grado di genotipizzare contemporaneamente un pannello così ampio. Il lavoro è stato finalizzato alla preparazione di un protocollo di laboratorio che permetta di studiare in modo efficace i 26 mHAgs identificati, per poi correlarli con GvHD/GvL all’interno di uno specifico gruppo di trapiantati. Utilizzando la metodica IPlex Gold Mass Array Sequenom e tecniche di biologia molecolare convenzionale sono stati genotipizzati 26 antigeni minori di istocompatibilità per 46 coppie full-matched. Tutti i pazienti inclusi nel progetto di studio erano stati sottoposti a trapianto allogenico di cellule staminali emopoietiche da donatore familiare o volontario full-compatibile per leucemia mieloide cronica (n=46) o leucemia acuta linfoblastica Philadelphia positiva (LAL-Ph+, n=24). Il progetto ha confermato l'efficienza (98.6%) e la fattibilità delle metodiche proposte. Dal lavoro è inoltre emerso che, le differenze tra donatore e ricevente a libello mHAgs ACC-1, ACC-4, ACC-5, LB-MTHFD1-1Q, UGT2B17, DPH1, LRH1 potrebbero essere fattori predittivi di GvHD (p<0.05). La seconda evidenza è legata a un trend secondo cui il mismatch per LB-ADIR1 protegge dalla recidiva di malattia, in particolare nei confronti della LAL-Ph+ che è scarsamente responsiva all'allo-immunoterapia. Questo lavoro pilota, la cui casistica deve quindi essere ampliata, ha dimostrato l’efficacia della genotipizzazione con IPlex Gold Sequenom e l’elevato potenziale degli mHAgs sia come fattori predittivi di GvHD che come driver di GvL.

Indicazione e risultati dei trattamenti locoregionali nell’epatocarcinoma

La chemioembolizzazione (TACE) è uno dei trattamenti locoregionali più largamente utilizzati nel trattamento dell’epatocarcinoma (HCC). A tutt’oggi però rimangono irrisolte alcune importanti controversie sul suo impiego. Nella presente tesi sono stati analizzati alcuni dei principali oggetti di dibattito quali (1) indicazione al trattamento, (2) trattamenti multipli e schema di ritrattamento e (3) trattamento dei pazienti candidabili a trapianto di fegato. A tal fine sono stati riportati tre studi che hanno analizzato gli argomenti sopradescritti. La TACE viene comunemente eseguita nei pazienti al di fuori delle raccomandazioni delle linee guida tra cui i pazienti con nodulo singolo, i pazienti con trombosi portale e con performance status (PS) compromesso. Dallo studio 1 è emerso che la TACE può essere considerata una valida opzione terapeutica nei pazienti con HCC singolo non candidabili a trattamenti curativi, che la trombosi portale non neoplastica ed una lieve compromissione del performance status (PS-1) verosimilmente legata alla cirrosi non hanno impatto sulla sopravvivenza post-trattamento. Multipli trattamenti di chemioembolizzazione vengono frequentemente eseguiti ma non esiste a tutt’oggi un numero ottimale di ritrattamenti TACE. Dallo studio 2 è emerso che il trattamento TACE eseguito “on demand” può essere efficacemente ripetuto nei pazienti che non abbiano scompenso funzionale e non siano candidabili a trattamenti curativi anche se solo una piccola percentuale di pazienti selezionati può essere sottoposto a più cicli di trattamento. La TACE è frequentemente impiegata nei pazienti in lista per trapianto di fegato ma non c’è evidenza dell’efficacia di trattamenti ripetuti in questi pazienti. Dallo studio 3 è emerso che il numero di TACE non è significativamente associato né alla necrosi tumorale, né alla recidiva né alla sopravvivenza post-trapianto. Un tempo d’attesa prima del trapianto ≤6 mesi è invece risultato essere fattore predittivo indipendente di recidiva riflettendo la possibile maggiore aggressività tumorale in questa classe di pazienti.

Cáncer y tratamiento oncológico: Representaciones sociales de la población general, el paciente oncológico y miembros del equipo de salud

Se realizaron tres estudios cualitativos que tuvieron como propósito conocer las representaciones que ha construido la población general, los pacientes oncológicos y los profesionales de la salud, sobre el cáncer, la quimioterapia y el trasplante de médula ósea y realizar un análisis sobre las semejanzas y diferencias entre ellos. Se realizó en la ciudad de Bogotá (Colombia) con 55 personas: 20 pacientes con cáncer en proceso de trasplante de médula ósea, 20 personas no diagnosticadas con cáncer y 15 personas que trabajan en la atención de pacientes con cáncer. Se realizó una entrevista en profundidad con todos los participantes y asociaciones libres, clásicas y por sustitución sobre las palabras “cáncer”, “quimioterapia” y “trasplante de médula”. Los datos conseguidos se analizaron a la luz de la Teoría de las Representaciones Sociales (TRS). El análisis de la información siguió la técnica de análisis cualitativo de contenido para encontrar significados simbólicos y construir, denominar y definir categorías. Para los tres grupos el cáncer es una enfermedad terrible, que puede llevar a la muerte. El personal de salud y la población general creen que la enfermedad genera terror, angustia y miedo. Los pacientes tienen conciencia de la gravedad y del temor consecuente por una enfermedad que lo cambia todo, produce sufrimiento, dolor, obliga a depender de alguien y puede conducir a la muerte. El personal de salud considera que los pacientes lo pueden vivir como un castigo y la población general que puede ser la consecuencia de estilos de vida poco saludables. Para todos, la quimioterapia es un tratamiento para la enfermedad, que por un lado presenta efectos colaterales difíciles y visibles y que producen sentimientos negativos de temor y de angustia y al mismo tiempo constituye una opción y posibilidad de curación. El Trasplante de Médula Ósea representa para todos una oportunidad.

A step forwards in immunomodulation and immunetolerance knowledge. HLA-G expression in co-cultures of peripheral blood mononuclear cells and stem cells after in vitro NGAL stimulation

NGAL (Neutrophil Gelatinase-associated Lipocalin ) is a protein of lipocalin superfamily. Recent literature focused on its biomarkers function in several pathological condition (acute and chronic kidney damage, autoimmune disease, malignancy). NGAL biological role is not well elucidated. Several are the demonstration of its bacteriostatic role. Recent papers have indeed highlight NGAL role in NFkB modulation. The aim of this study is to understand whether NGAL may exert a role in the activation (modulation) of T cell response through the regulation of HLA-G complex, a mediator of tolerance. From 8 healthy donors we obtained peripheral blood mononuclear cells (PBMCs) and we isolated by centrifugation on a Ficoll gradient. Cells were then treated with four concentrations of NGAL (40-320 ng/ml) with or without iron. We performed flow cytometry analysis and ELISA test. NGAL increased the HLA-G expression on CD4+ T cells, with an increasing corresponding to the dose. Iron effect is not of unique interpretation. NGAL adiction affects regulatory T cells increasing in vitro expansion of CD4+ CD25+ FoxP3+ cells. Neutralizing antibody against NGAL decreased HLA-G expression and reduced significantly CD4+ CD25+ FoxP3+ cells percentage. In conclusion, we provided in vitro evidence of NGAL involvement in cellular immunity. The potential role of NGAL as an immunomodulatory molecule has been evaluated: it has been shown that NGAL plays a pivotal role in the induction of immune tolerance up regulating HLA-G and T regulatory cells expression in healthy donors. As potential future scenario we highlight the in vivo role of NGAL in immunology and immunomodulation, and its possible relationship with immunosuppressive therapy efficacy, tolerance induction in transplant patients, and/or in other immunological disorders.

La fotochemioterapia extracorporea (ECP) nel trattamento delle glomerulonefriti

I pazienti con glomerulopatie con sindrome nefrosica hanno poche opzioni di trattamento efficace. Riportiamo la nostra esperienza sull'utilizzo della fotochemioterapia extracorporea ( ECP) in 9 pazienti in cui non era stata osservata una risposta efficace/duratura alla convenzionale terapia farmacologica. L’ECP è una promettente terapia immunomodulante, che è stata utilizzata con successo nel trattamento di altre condizioni immunomediate come il rigetto nel trapianto e il GvHD. METODI: In questo studio abbiamo arruolato 9 pazienti, 5 maschi e 4 femmine, età media 32.7±8.9 anni, affetti da sindrome nefrosica e non responsivi/resistenti alle comuni terapie. Il follow-up medio è stato di 41.3±21.7 mesi. Tutti i pazienti sono stati sottoposti a cicli di fotochemioterapia extracorporea secondo il seguente schema: 1ciclo (2 sedute in 2 giorni consecutivi) ogni 15 giorni per tre mesi, seguito da 1ciclo al mese per tre mesi. Il follow up è stato effetuatio ogni 3 mesi durante il primo anno e poi ogni 12 mesi. Durante il follow up sono stati monitorati pressione arteriosa, funzione renale, marcatori diretti ed indiretti di attività della malattia e indici di flogosi. RISULTATI: attraverso l'analisi dei parametri ematochimici indici di attività di malattia, e monitorando l'eventuale progressione della malattia renale, è stato possibile dimostrare che l' ECP può rappresentare per casi selezionati di pazienti una valida ulteriore opzione terapeutica. Secondo i risultati preliminari tale trattamento risulta inoltre caratterizzato da un eccellente profilo di sicurezza . CONCLUSIONI: I risultati osservati suggeriscono che l’ECP è un trattamento efficace per i pazienti con glomenulonefriti con sindrome nefrosica, soprattutto in coloro che presentano ancora una buona funzionalità renale. Valutazioni cliniche aggiuntive dovranno aiuteranno a definire meglio la popolazione di pazienti in cui ECP sia più efficace e raccomandabile.

Simkania negevensis: clinical and laboratory studies in the population of hemodialized and kidney transplanted patients.

Simkania negevensis is a bacterium belonging to the order Chlamydiales but with certain biological characteristics different from those of chlamydia, according to which it was classified in the family Simkaniaceae. It is widespread in the environment, due to its ability to survive in amoebae also in phase cystic, for which it was hypothesized a possible transmission after contact with water in which they are present amoebae. So far it is known its role in diseases of the lower respiratory tract, such as childhood bronchiolitis and pneumonia in adults of the community, following its transmission through infected aerosols. A recent American study showed, by PCR, a high prevalence of S. negevensis in patients with lung transplant than other transplant recipients, assuming an association between the presence of the bacterium in these patients, and transplant rejection, were more frequent in lung transplant recipients infected compared to uninfected. There are no data so far analyzed in Italy relative to the population of dialysis and kidney transplant recipients relative to simkania negevensis why this study was undertaken in order to start a specific location and evaluate the scientific implications. Because its ability to assume persistent forms of infection, which may lead to a prolonged inflammatory response, Simkania negevensis, similar to other persistent bacteria or viruses, may be ivolved in pathologic complication. Sn may be a factor in graft rejection in mmunesuppressed lung transplant recipients, and further studies are planned to explore the posible association of Sn infections with various in vivo pathologies.