Effects of Chronic Factor VIII Substitution on Immune Parameters in HIV Seronegative Haemophiliacs: a Comparison between Cryoprecipitate and Factor VIII Concentrate

1996 ◽  
Vol 75 (02) ◽  
pp. 261-266 ◽  
Author(s):  
D P Allersmaa ◽  
W M Smld ◽  
J A van der Does ◽  
J van der Meer ◽  
E Briët
Keyword(s):  
Factor Viii ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Activated T Cells ◽  
Immune Parameters ◽  
Hla Dr ◽  
Factor Viii Concentrates ◽  
Patient Groups ◽  
Previously Treated ◽  
Hiv Negative

SummaryChronic substitution therapy of HIV-negative haemophiliacs with factor VIII products can result in abnormalities of ex-vivo measured immune parameters. To assess a possible relation between these abnormalities and product purity, we analyzed two groups of HIV-negative HCV-positive haemophiliacs, one treated with cryoprecipitate exclusively, the other with more purified factor VIII concentrates. Compared to age matched non-transfused male controls, increased numbers of white cells, granulocytes, IgG and IgM levels and decreased CD4+/CD8+ ratios were found in both patient groups. In the concentrate receivers, the numbers of mononuclear cells, CD4+, CD8+ and CD3+/HLA-DR+ cells indicating activated T-cells, were higher than in the cryoprecipitate group. In conclusion, both cryoprecipitate and intermediate/high purity concentrate recipients showed immune parameter abnormalities. These abnormalities tended to be somewhat more pronounced in patients treated with concentrates. By now there is no indication of the clinical relevance of the abnormalities in previously treated HIV seronegative haemophiliacs.

The Course of Preexistent Immune Abnormalities in HIV Negative Haemophiliacs Treated for Two Years with a Monoclonal Purified Factor VIII Concentrate

1993 ◽  
Vol 69 (04) ◽  
pp. 306-310 ◽  
Author(s):  
W M Smid ◽  
J van der Meer ◽  
J W Smit ◽  
M R Halie
Keyword(s):  
Hiv Infection ◽  
Factor Viii ◽  
B Lymphocytes ◽  
Skin Tests ◽  
First Year ◽  
Severe Haemophilia ◽  
Hla Dr ◽  
Serologic Evidence ◽  
Factor Viii Concentrates ◽  
Hiv Negative

SummaryThe administration of factor VIII concentrates has been associated with immune abnormalities in patients with severe haemophilia A, even in the absence of HIV infection.The effects of a monoclonal purified factor VIII concentrate, Hemofil M (Baxter), on preexistent immune abnormalities were assessed over a 2 year period in 22 HIV negative haemophiliacs. They were treated previously with other concentrates, and received Hemofil T from 1983 to 1988. No HIV infection was demonstrated. No serologic evidence for other viral (re)-infections was seen. A decrease of HLA-DR expression on non-B lymphocytes in the first year (P = 0.026), and a decrease of T4-T8 ratio over the 2 years were found (P = 0.0016). Skin tests were non-contributive. The decrease in HLA-DR expression is suggestive for an improved immune function, possibly due to a reduced content of protein or virus in this concentrate.

F VIII Inhibitors in Haemophilia A Patients who Are Considered as Previously Treated Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4022-4022
Author(s):  
Ch. von Auer ◽  
M. Krause ◽  
W. Miesbach ◽  
I. Scharrer ◽  
G. Asmelash ◽  
...  
Keyword(s):  
Factor Viii ◽  
Haemophilia A ◽  
Missense Mutations ◽  
Genotype 4 ◽  
Large Deletions ◽  
Factor Viii Concentrates ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Factor Concentrate ◽  
Continuous Use

Abstract Previously treated patients (PTP), who have not developed an inhibitor (inh) so far, are considered to be tolerant to factor VIII and at low risk for inh development. Therefore inh detection in a PTP should raise concerns about the concomitant variables such as product neo-antigenicity or way of application. In our own center we recently detected the new development of a high responding inh to factor VIII in a 58 year old patient with severe haemophilia A. To find out about the current situation regarding inh development in PTP in Germany, we conducted a retrospective study. A questionnaire was sent to 99 haemophilia treating physicians, so far 46 of them answered. 24 PTP-inh were registered during the last 5 years. Patients had at least 20 ED and/or one change of factor concentrate. Age (9 months to 70 years, median 35), severity of haemophilia A (16 severe, 2 moderate, 6 mild), exposure days (ED 6 to >1500, median 37) and genotype (4 intron-22-inversions, 3 large deletions, 2 missense mutations, 1 stop mutation, 1 insertion, 1 small deletion, 11 unknown) were recorded. 8 different factor VIII concentrates were given during inh development (5 plasma derived, 3 recombinant). Way of application (16 bolus infusion, 3 continuous infusion, 5 times both), infused amount until inh development (3000 IU to >1 mio IU), inh characteristic (15 HR, 9 LR), concomitant diseases and medication were registered. In conclusion it became obvious that inh in PTP are still a serious and underestimated problem in haemophilia treatment today. Our patient numbers are still too small to draw conclusions concerning given F VIII products or way of application. Secondly data showed that there is a variety of PTP definitions in Germany, referring to age of pat, number of ED and former change of product. A definition from the SSC of the ISTH for PTP would be helpful. The continuous use of the German register for drug side effects would make it easier to evaluate data in the future. A prospective, not product related study should be conducted.

scholarly journals Binding and Transfer of Human Immunodeficiency Virus by DC-SIGN+ Cells in Human Rectal Mucosa

2005 ◽  
Vol 79 (9) ◽  
pp. 5762-5773 ◽  
Author(s):  
Kevin B. Gurney ◽  
Julie Elliott ◽  
Hoorig Nassanian ◽  
Carol Song ◽  
Elizabeth Soilleux ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Rectal Mucosa ◽  
Virus Binding ◽  
Mucosal Transmission ◽  
Hla Dr ◽  
Immunodeficiency Virus

ABSTRACT The role of DC-SIGN on human rectal mucosal dendritic cells is unknown. Using highly purified human rectal mucosal DC-SIGN+ cells and an ultrasensitive real-time reverse transcription-PCR assay to quantify virus binding, we found that HLA-DR+/DC-SIGN+ cells can bind and transfer more virus than the HLA-DR+/DC-SIGN− cells. Greater than 90% of the virus bound to total mucosal mononuclear cells (MMCs) was accounted for by the DC-SIGN+ cells, which comprise only 1 to 5% of total MMCs. Significantly, anti-DC-SIGN antibodies blocked 90% of the virus binding when more-physiologic amounts of virus inoculum were used. DC-SIGN expression in the rectal mucosa was significantly correlated with the interleukin-10 (IL-10)/IL-12 ratio (r = 0.58, P < 0.002; n = 26) among human immunodeficiency virus (HIV)-positive patients. Ex vivo and in vitro data implicate the role of IL-10 in upregulating DC-SIGN expression and downregulating expression of the costimulatory molecules CD80/CD86. Dendritic cells derived from monocytes (MDDCs) in the presence of IL-10 render the MDDCs less responsive to maturation stimuli, such as lipopolysaccharide and tumor necrosis factor alpha, and migration to the CCR7 ligand macrophage inflammatory protein 3β. Thus, an increased IL-10 environment could render DC-SIGN+ cells less immunostimulatory and migratory, thereby dampening an effective immune response. DC-SIGN and the IL-10/IL-12 axis may play significant roles in the mucosal transmission and pathogenesis of HIV type 1.

Anti-CD3 Activated T Cells from Cord Blood Can Be Expanded Ex Vivo and Armed with Bispecific Antibodies To Lyse Her2/Neu + and CD20+ Targets: A Strategy for Providing Anti-Tumor/Lymphoma Effects after Cord Blood Transplant.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2751-2751
Author(s):  
Carly B. Sorenson ◽  
Thomas D. Frandsen ◽  
Suanne Dorr ◽  
Voravit Ratanatharathorn ◽  
Joseph P. Uberti ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Transplant ◽  
Activated T Cells ◽  
Specific Cytotoxicity ◽  
The Mean

Abstract Our previous studies showed that anti-CD3 activated T cells (ATC) from peripheral blood mononuclear cells could be expanded in interleukin-2 (IL-2) for 14 days and armed with anti-CD3 x anti-Her2/neu (Her2Bi)[J Hemat & Stem Cell Res10:247,2001], anti-CD3 x anti-CD20 (CD20Bi)[Exp Hemat33:452,2005], or anti-CD3 x anti-EGFR [Clin Cancer Res12:183,2006] bispecific antibody (BiAb)and can kill Her2/neu, CD20, and EGFR+ tumor targets, respectively. In this study, we asked whether anti-CD3 activated cord blood T cells (CBATC) could be expanded and targeted with Her2Bi and CD20Bi to tumors or hematologic malignancies for infusions after cord blood stem cell transplant (CBSCT). CB mononuclear cells were activated with anti-CD3 (20 ng/ml) and expanded for 14 days in IL-2 (100 IU/ml). CBATC were armed with Her2Bi or CD20Bi and tested for specific cytotoxicity directed SK-BR-3, Raji, or B9C targets and cytokine secretion or IFNγ EliSpots after binding to tumor cells. Our results show the mean expansion of CBATC to be 43-fold (n=8) after 14 days of culture. By the end of culture, the proportions of CD8+ and CD4+ were 82% and 18%, respectively. The proportion of cells expressing CD19 or CD20 did not exceed 6.3%, CD56+ cells were <3.6% and CD3-CD16+CD56+ cells was <0.7%. Cells positive for CD4+CD25+ or CD8+ CD25+ were 4.2% or 7.1%, respectively (n=2). Specific cytotoxicity was optimized when CBATC were armed with 50 ng/106 cells of Her2Bi or CD20Bi (arming dose ranged from 5, 50, and 500 ng/106 cells); arming significantly increased cytotoxicity of the armed CBATC over that seen for unarmed CBATC. Cytotoxicity peaked between days 12 and 14 for both BiAbs. The ability of CD20Bi armed ATC to produce Elispots for IFNγ were tested by arming ATC the CD20Bi after 0, 8, 11, and 13 days of culture peaked on day 8. Only CD20+ targets induced Elispots and day 8 armed ATC exhibited peak numbers (2,200 Elispots(ranged from 1,700 to 1,800 on day 8)/106 armed ATC plated). At an effector/target ratio (E:T) of 25:1, the mean cytotoxicity of CBATC armed with Her2Bi or CD20Bi was 60% (n=4) and 35% (n=1), respectively. In an extended culture to day 47, mean cytotoxicity for Her2Bi-armed CBATC was 36% at an E/T of 25:1 compared to 4.35% for unarmed CBATC. Unarmed CBATC did not kill Daudi targets. Armed CBATC mediated both specific cytotoxicity and secreted IFN-γ as measured by ELISA or EliSpots. Both fresh and frozen CB could be used in the assays. In a clinical application, specific cytotoxicity of armed CBATC could be used to augment anti-tumor and anti-lymphoma effects after CBSCT.

Factor VIII Inhibitors in Previously Treated Haemophilia A Patients with a Double Virus-inactivated Plasma Derived Factor VIII Concentrate

1997 ◽  
Vol 77 (01) ◽  
pp. 080-086 ◽  
Author(s):  
K Peerlinck ◽  
J Arnout ◽  
M Di Giambattista ◽  
J G Gilles ◽  
R Laub ◽  
...  
Keyword(s):  
Factor Viii ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Inhibition Kinetics ◽  
Factor Viii Concentrates ◽  
Detergent Treatment ◽  
Previously Treated ◽  
Associated Risk Factors ◽  
Factor Concentrate ◽  
Second Category

SummaryAntibodies to factor VIII (inhibitors) are usually produced at the beginning of treatment with factor VIII and are rare in multitransfused patients. Such antibodies are deemed to be patient-related, as supported by the description of a number of associated risk factors. However, a second category of inhibitors has recently been identified, namely antibodies occurring in multitransfused patients as a result of exposure to a particular factor VIII concentrate. A first outbreak of product-related inhibitors was recently described. The present paper describes the second well-documented occurrence of such inhibitors.Eight out of 140 multitransfused patients with severe haemophilia A developed an inhibitor to factor VIII shortly after changing treatment to a double-virus inactivated plasma-derived factor VIII concentrate. In addition to solvent-detergent treatment, this concentrate was pasteurised at 63° C for 10 hours. Exposure to the pasteurised product before inhibitor detection ranged from 9 to 45 days. Inhibitor titers varied between 2.2 and 60 Bethesda Units and recovery of transfused factor VIII ranged from 0.21 to 0.68 (expressed as IU/dl factor VIII rise per IU/kg administered). In contrast to usual inhibitors in haemophilia A patients, these product-related inhibitors showed complex inhibition kinetics. They were found specific for the factor VIII light chain. The inhibitors gradually declined when exposure to the pasteurised product was stopped, despite further treatment with other factor VIII concentrates. The present data stress the importance of carefully monitored clinical studies, both in previously treated and previously untreated patients, before introduction of a new or modified clotting factor concentrate.

scholarly journals Antibiotics Differentially Modulate Lipoteichoic Acid-Mediated Host Immune Response

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 573
Author(s):  
Marquerita Algorri ◽  
Annie Wong-Beringer
Keyword(s):  
Immune Response ◽  
Cell Surface ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Lipoteichoic Acid ◽  
Cytokine Response ◽  
Hla Dr

In Staphylococcus aureus bacteremia, our group has shown that a dysregulated balance of pro- and anti-inflammatory cytokine response biased towards an immunoparalysis phenotype is predictive of persistence and mortality, despite receipt of antibiotics. Certain antibiotics, as well as lipoteichoic acid (LTA) released from S. aureus, can modulate immune response ex vivo. Here, we evaluated the effects of three anti-staphylococcal antibiotics (vancomycin, tedizolid, and daptomycin) on the expression of cytokines and cell surface markers of immune activation (TNFα, HLA-DR) and immunoparalysis (IL-10, PD-L1) in human peripheral blood mononuclear cells (PBMC) exposed to high (10 μg) and low (1 μg) doses of LTA. Results suggested a dose-dependent relationship between LTA and induction of anti- and pro-inflammatory immune responses. Differential antibiotic effects were prominently observed at high but not low LTA condition. Vancomycin significantly induced IL-10 and TNFα expression, whereas daptomycin had no effects on cytokine response or expression of cell surface receptors. Tedizolid increased TNFα and modestly increased HLA-DR expression, suggesting a stimulatory effect. These findings suggest that anti-staphylococcal agents differentially alter LTA-mediated immune cell activation status and cytokine response, providing support for future clinical studies to better elucidate the complexities of host–microbial–antibiotic interaction that can help direct precision therapy for S. aureus bacteremia.

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