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Katie Matthews,
ZiYi Lim,
Behdad Afzali,
Laurence Pearce, Atiyeh Abdallah,
Shahram Kordasti,
Antonio Pagliuca,
Giovanna Lombardi,
J Alejandro Madrigal,
Ghulam J Mufti,
Linda D Barber
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ABSTRACT: A variety of immune pathways can lead to graft-versus-host disease. A better understanding of the type of immune response causing graft-versus-host disease in defined clinical hematopoietic stem cell transplant settings is required to inform development of methods for monitoring patients and providing them tailored care.
Twenty-five patients were recruited presenting with myeloid malignancies and treated with a reduced intensity conditioning transplant regimen with graft-versus-host disease prophylaxis comprising in vivo lymphocyte depletion with alemtuzumab and cyclosporin. A prospective study was performed of lymphocyte subset reconstitution in peripheral blood in relation to the incidence of graft-versus-host disease.
Acute graft-versus-host disease was associated with significantly higher numbers of natural killer cells and donor-derived effector CD4 T cells (CD45RO(+) CD27(-)) early (day 30) after transplantation (p=0.04 and p=0.02, respectively). This association was evident before the emergence of clinical pathology in six out of seven patients. Although numbers of regulatory CD4 T cells (CD25(high) Foxp3(+)) were similar at day 30 in all patients, a significant deficit in those who developed acute graft-versus-host disease was apparent relative to effector CD4 T cells (median of 41 effectors per regulatory cell compared to 12 to 1 for patients without graft-versus-host disease) (p=0.03). By day 180, a functional regulatory CD4 T-cell population had expanded significantly in patients who developed chronic graft-versus-host disease, reversing the imbalance (median of 3 effectors per regulatory cell compared to 9.6 to 1 for patients without graft-versus-host disease) (p=0.018) suggesting no overt absence of immune regulation in the late onset form of the disease.
Imbalance of effector and regulatory CD4 T cells is a signature of graft-versus-host disease in this transplantation protocol.
Haematologica 07/2009; 94(7):956-66. · 6.42 Impact Factor
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ABSTRACT: Haemopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) has been associated with delayed disappearance of host anti-A and anti-B isohaemaglutinins and hindrance of donor erythropoiesis in major ABO mismatched transplants. Erythroid recovery, disappearance of recipient type and appearance of donor-type isohaemaglutinins was compared in 84 patients undergoing RIC and 50 patients with standard-conditioning (SCo) HCT. All patients received alemtuzumab as part of their conditioning. The incidence of immune-mediated anaemia and red cell transfusion usage were also compared. Immune factors affecting post-transplant erythroid kinetics showed little variance between different conditioning regimens. Disappearance of recipient isohaemaglutinins and emergence of donor red cells proceeded at similar rates in RIC and SCo transplants; the effects of ABO mismatch were marginal. Pure red cell aplasia, alloimmune haemolysis and autoimmune haemolytic anaemia were not more common in RIC transplants. We believe that alemtuzumab played a critical role in dampening immune reactions of both the host and the donor. Patients in both conditioning groups had similar post-transplant erythroid burst-forming unit (BFU-E) counts; BFU-E chimaerism analysis showed that 90-100% progenitors were of donor origin. However, transfusion requirements were significantly higher in the SCo group, due at least partly to earlier onset of bone marrow hypoplasia.
British Journal of Haematology 06/2008; 142(3):444-52. · 4.94 Impact Factor
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ABSTRACT: Chemokines are important inflammatory mediators that play a crucial role in uveitis. Polymorphisms in chemokine genes can alter the expression of these genes in the inflammatory cells, which, in turn, can affect the clinical phenotype of the disease. The purpose of this study was to identify polymorphisms in chemokine genes that can predict visual outcome in patients with immune-mediated posterior segment uveitis.
This is a case-control study of 141 Caucasians with idiopathic immune-mediated posterior segment uveitis and 282 controls matched by age and ethnicity. Six polymorphisms in four genes, (MCP-1-2518A/G, RANTES-403G/A, RANTES-28C/G, CCR2 V64I, CCR5-59029G/A, and CCR5 32 bp deletion) were analyzed by sequence specific primers polymerase chain reaction.
Patients with G allele at MCP-1-2581 developed the disease at an early age as compared to patients with A allele corrected p value pc=0.003. Also patients with A allele at RANTES-403 position developed less severe disease and had better visual outcome when compared with patients with G allele (pc=0.02) Final visual acuity after 18 months was better in patients with 32 bp deletion of the CCR5 gene and in patients with the CCR2 wild-type genotype pc=0.02 and pc=0.04, respectively. Patients with the CCR2 64I allele also had a higher risk of developing an elevated intraocular pressure as compared to patients with the wild-type genotype (pc=0.007).
Though the utility for prediction of disease susceptibility of the studied polymorphisms in chemokine genes is in general not robust, we have found that polymorphisms in chemokine genes can influence the outcome of patients with idiopathic immune-mediated posterior segment uveitis. These associations require further analysis in other groups of patients.
Molecular vision 02/2007; 13:388-96. · 2.20 Impact Factor
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Paolo Spagnolo,
Elisabetta A Renzoni,
Athol U Wells,
Susan J Copley,
Sujal R Desai,
Hiroe Sato,
Jan C Grutters, Atiyeh Abdallah,
Anne Taegtmeyer,
Roland M du Bois,
Kenneth I Welsh
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ABSTRACT: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin.
We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells.
In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects.
In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage >or= II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96-13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5-17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5-18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8-16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5-23.1; corrected p = 0.0009).
No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.
American Journal of Respiratory and Critical Care Medicine 10/2005; 172(6):721-8. · 11.08 Impact Factor
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Paolo Spagnolo,
Elisabetta A Renzoni,
Athol U Wells,
Hiroe Sato,
Jan C Grutters,
Piersante Sestini, Atiyeh Abdallah,
Enzo Gramiccioni,
Henk J T Ruven,
Roland M du Bois,
Kenneth I Welsh
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ABSTRACT: Sarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-Löfgren sarcoidosis, 47 Löfgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1-9). In patients with Löfgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-Löfgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and Löfgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for Löfgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and Löfgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.
American Journal of Respiratory and Critical Care Medicine 12/2003; 168(10):1162-6. · 11.08 Impact Factor
