- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03111589
Monocytic Expression of Heme Oxidase-1 (HO-1) in Sickle Cell Patients and Correlation With the Humoral Immune Response to Vaccine and With Allo-immunization.
Monocytic Expression of Heme Oxidase-1 (HO-1) in Sickle Cell Patients and Correlation With the Humoral Immune Response to Vaccine and With Allo-immunization
Sickle cell disease (SCD) is an autosomal recessive disorder resulting from a substitution in the β chain of hemoglobin (Hb) which causes hemoglobin S to polymerize when deoxygenated. SCD patients present immune abnormalities that have always been attributed to functional asplenia. It it is now being recognized that patients with SCD have a pro-inflammatory condition with altered immune system activation contributing to the pathology of SCD. Increased levels of neutrophils, monocytes or cytokines have been reported in SCD patients.
SCD is associated with many acute and chronic complications requiring immediate support. Actual strongly recommended therapies include chronic blood transfusions (CT) and hydroxyurea (HU). In addition, episodic transfusions are recommended and commonly used to manage many acute SCD complications.There is strong evidence to support the use of HU in adults with 3 or more severe vaso-occlusive crises during any 12-month period, with SCD pain or chronic anemia, or with severe or recurrent episodes of acute chest syndrome. HU use is now also common in children with SCD. Some patients receive chronic monthly RBC transfusion with the objective to reduce the proportion of HbS to < 30 %. Long-term RBC transfusions prevent and treat complications of SCD decreasing the risk of stroke and the incidence of acute chest syndrome (ACS).
Therapeutic complications, such as alloimmunization against RBC in 20-50% of patients or hematopoietic stem cell transplantation (HSCT) graft rejection, constitute an immune-based clinical issue in SCD. Poorly understood RBC alloimmunization is responsible for serious hemolytic transfusion reaction associated with severe mortality and morbidity underlying the need for a better understanding of the immunology of SCD to improve SCD transfusion support/outcome. Little evidence exists about HU effects on immune functions in SCD. HU treatment doesn't appear to have deleterious effects on immune function and appears to decrease the abnormally elevated number of total WBC and lymphocytes, while CT does not.
Patients with SCD are at higher risk of infections and prophylactic vaccination is strongly recommended. Recent data suggest that vaccinal response to pneumococcal antigens in SCD patients is identical to healthy control while controversy concern the stability of the immune protection after vaccination of SCD patient. Antibody levels declined over the year and the need for more frequent vaccination in SCD patient should be investigated. Currently, there is no evidence whether HU may interfere with pneumococcal immune response. Purohit showed that immune response to inactivated influenza A (H1N1) virus vaccine was altered in patient with SCD receiving CT but little is known on immune response to vaccination in patients with SCD receiving HU.
Recent data suggest that not only inflammatory status but also humoral immune response to antigens in SCD patients may differ according to treatment. Yazdanbakhsh reported an imbalance between regulatory T cell (Treg) and effector T cell (Teff) in alloimmunized SCD patients with as consequence an increase in antibody production. In a model proposed by the authors, the balance between Treg and Teff is dictated by the monocyte control of cytokines expression. Altered activity of monocyte heme oxidase-1 (HO-1) would be responsible of a decrease in IL-12 and an increase in IL-10 cytokines secretion impacting the Treg/Teff cells ratio and promoting antibody production by B cells.
The objectives of the project are to assess whether different humoral immune responses to vaccines or to erythrocyte alloantigens are related to the type of treatment administered to patients with SCD. We also aim to study if these differences might be related to different expressions of HO-1 by monocytes.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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-
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Brussels, Belgium, 1020
- CHU Brugmann
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Brussels, Belgium, 1020
- Huderf
-
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Pediatric and adult patients with sickle cell disease from the HUDERF and CHU-Brugmann Hospital
Exclusion Criteria:
- None
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: SCD patients under regular chronic exchange transfusion
Sickle cell disease patients (SCD) under regular chronic exchange transfusions.
Pediatric and adult patients from the HUDERF and CHU-Brugmann Hospitals.
|
All groups of patients and the control group will receive the new annually recommended inactivated influenza A (H1N1) virus vaccine.
Testing of the different humoral immune responses to vaccines or to erythrocyte alloantigens.
|
Experimental: SCD patients under HU treatment alone
Sickle cell disease patients (SCD) under hydroxyurea (HU) alone.
Pediatric and adult patients from the HUDERF and CHU-Brugmann Hospitals.
|
All groups of patients and the control group will receive the new annually recommended inactivated influenza A (H1N1) virus vaccine.
Testing of the different humoral immune responses to vaccines or to erythrocyte alloantigens.
|
Experimental: SCD patients under HU treatment+sporadic transfusion
Sickle cell disease patients (SCD) under hydroxyurea (HU) and receiving sporadic transfusions.Pediatric and adult patients from the HUDERF and CHU-Brugmann Hospitals.
|
All groups of patients and the control group will receive the new annually recommended inactivated influenza A (H1N1) virus vaccine.
Testing of the different humoral immune responses to vaccines or to erythrocyte alloantigens.
|
Active Comparator: Control group
Pediatric and adult patients from the HUDERF and CHU-Brugmann Hospitals.
|
All groups of patients and the control group will receive the new annually recommended inactivated influenza A (H1N1) virus vaccine.
Testing of the different humoral immune responses to vaccines or to erythrocyte alloantigens.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intracellular HO-1 expression in monocytes
Time Frame: 1 month post vaccination
|
Intracellular monocyte heme oxidase-1 (HO-1) expression will be measured by flow cytometry.The protein expression of HO-1 will be confirmed by Western blot.
A commercial ELISA kit will be used in parallel to assess HO-1 levels in PBMC cell lysate.
|
1 month post vaccination
|
HO-1 level in serum
Time Frame: 1 month post vaccination
|
Monocyte heme oxidase-1 (HO-1) level in serum will be measured by a commercial ELISA kit
|
1 month post vaccination
|
Cytokines levels measurement
Time Frame: 1 month post vaccination
|
Pro-inflammatory cytokine (IL-12) and anti-inflammatory cytokine (IL-10) levels will be evaluated in serum and in IL-1 stimulated whole blood supernatants using an ELISA assay.
|
1 month post vaccination
|
Identification of T regulatory cells
Time Frame: 1 month post vaccination
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Evaluation of Treg cells in peripheral blood mononuclear cells (PBMC) will be performed by flow cytometry using appropriate fluorochrome conjugated monoclonal antibodies for CD25 and FoxP3 markers
|
1 month post vaccination
|
Immune response to vaccination
Time Frame: 1 month post vaccination
|
Post-vaccination serum H1N1 antibodies titers (IgG and IgM) will be measured by an ELISA kit
|
1 month post vaccination
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intracellular HO-1 expression in monocytes
Time Frame: Baseline: at vaccination
|
Intracellular HO-1 expression will be measured by flow cytometry.The protein expression of HO-1 will be confirmed by Western blot.
A commercial ELISA kit will be used in parallel to assess HO-1 levels in PBMC cell lysate.
|
Baseline: at vaccination
|
Intracellular HO-1 expression in monocytes
Time Frame: 3 months post vaccination
|
Intracellular HO-1 expression will be measured by flow cytometry.The protein expression of HO-1 will be confirmed by Western blot.
A commercial ELISA kit will be used in parallel to assess HO-1 levels in PBMC cell lysate.
|
3 months post vaccination
|
Intracellular HO-1 expression in monocytes
Time Frame: 6 months post vaccination
|
Intracellular HO-1 expression will be measured by flow cytometry.The protein expression of HO-1 will be confirmed by Western blot.
A commercial ELISA kit will be used in parallel to assess HO-1 levels in PBMC cell lysate.
|
6 months post vaccination
|
HO-1 level in serum
Time Frame: Baseline: at vaccination
|
HO-1 level in serum will be measured by a commercial ELISA kit
|
Baseline: at vaccination
|
HO-1 level in serum
Time Frame: 3 months post vaccination
|
HO-1 level in serum will be measured by a commercial ELISA kit
|
3 months post vaccination
|
HO-1 level in serum
Time Frame: 6 months post vaccination
|
HO-1 level in serum will be measured by a commercial ELISA kit
|
6 months post vaccination
|
Cytokines levels measurement
Time Frame: Baseline: at vaccination
|
Pro-inflammatory cytokine (IL-12) and anti-inflammatory cytokine (IL-10) levels will be evaluated in serum and in IL-1 stimulated whole blood supernatants using an ELISA assay.
|
Baseline: at vaccination
|
Cytokines levels measurement
Time Frame: 3 months post vaccination
|
Pro-inflammatory cytokine (IL-12) and anti-inflammatory cytokine (IL-10) levels will be evaluated in serum and in IL-1 stimulated whole blood supernatants using an ELISA assay.
|
3 months post vaccination
|
Cytokines levels measurement
Time Frame: 6 months post vaccination
|
Pro-inflammatory cytokine (IL-12) and anti-inflammatory cytokine (IL-10) levels will be evaluated in serum and in IL-1 stimulated whole blood supernatants using an ELISA assay.
|
6 months post vaccination
|
Identification of T regulatory cells
Time Frame: Baseline: at vaccination
|
Evaluation of Treg cells in PBMC will be performed by flow cytometry using appropriate fluorochrome conjugated monoclonal antibodies for CD25 and FoxP3 markers
|
Baseline: at vaccination
|
Identification of T regulatory cells
Time Frame: 3 months post vaccination
|
Evaluation of Treg cells in PBMC will be performed by flow cytometry using appropriate fluorochrome conjugated monoclonal antibodies for CD25 and FoxP3 markers
|
3 months post vaccination
|
Identification of T regulatory cells
Time Frame: 6 months post vaccination
|
Evaluation of Treg cells in PBMC will be performed by flow cytometry using appropriate fluorochrome conjugated monoclonal antibodies for CD25 and FoxP3 markers
|
6 months post vaccination
|
Immune response to vaccination
Time Frame: Baseline: at vaccination
|
Post-vaccination serum H1N1 antibodies titers (IgG and IgM) will be measured by an ELISA kit
|
Baseline: at vaccination
|
Immune response to vaccination
Time Frame: 3 months post vaccination
|
Post-vaccination serum H1N1 antibodies titers (IgG and IgM) will be measured by an ELISA kit
|
3 months post vaccination
|
Immune response to vaccination
Time Frame: 6 months post vaccination
|
Post-vaccination serum H1N1 antibodies titers (IgG and IgM) will be measured by an ELISA kit
|
6 months post vaccination
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Francis Corazza, MD, CHU Brugmann
Publications and helpful links
General Publications
- Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. doi: 10.1001/jama.2014.10517. Erratum In: JAMA. 2014 Nov 12;312(18):1932. JAMA. 2015 Feb 17;313(7):729.
- Chintagari NR, Nguyen J, Belcher JD, Vercellotti GM, Alayash AI. Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease. Blood Cells Mol Dis. 2015 Mar;54(3):302-6. doi: 10.1016/j.bcmd.2014.12.001. Epub 2014 Dec 22.
- Cunnington AJ, Njie M, Correa S, Takem EN, Riley EM, Walther M. Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction. J Immunol. 2012 Dec 1;189(11):5336-46. doi: 10.4049/jimmunol.1201028. Epub 2012 Oct 24.
- De Montalembert M, Abboud MR, Fiquet A, Inati A, Lebensburger JD, Kaddah N, Mokhtar G, Piga A, Halasa N, Inusa B, Rees DC, Heath PT, Telfer P, Driscoll C, Al Hajjar S, Tozzi A, Jiang Q, Emini EA, Gruber WC, Gurtman A, Scott DA. 13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study. Pediatr Blood Cancer. 2015 Aug;62(8):1427-36. doi: 10.1002/pbc.25502. Epub 2015 Mar 23. Erratum In: Pediatr Blood Cancer. 2019 Feb;66(2):e27554.
- Hankins J, Jeng M, Harris S, Li CS, Liu T, Wang W. Chronic transfusion therapy for children with sickle cell disease and recurrent acute chest syndrome. J Pediatr Hematol Oncol. 2005 Mar;27(3):158-61. doi: 10.1097/01.mph.0000157789.73706.53.
- Lanaro C, Franco-Penteado CF, Albuqueque DM, Saad ST, Conran N, Costa FF. Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol. 2009 Feb;85(2):235-42. doi: 10.1189/jlb.0708445. Epub 2008 Nov 12.
- Lederman HM, Connolly MA, Kalpatthi R, Ware RE, Wang WC, Luchtman-Jones L, Waclawiw M, Goldsmith JC, Swift A, Casella JF; BABY HUG Investigators. Immunologic effects of hydroxyurea in sickle cell anemia. Pediatrics. 2014 Oct;134(4):686-95. doi: 10.1542/peds.2014-0571. Epub 2014 Sep 1.
- Mohri T, Ogura H, Koh T, Fujita K, Sumi Y, Yoshiya K, Matsushima A, Hosotsubo H, Kuwagata Y, Tanaka H, Shimazu T, Sugimoto H. Enhanced expression of intracellular heme oxygenase-1 in deactivated monocytes from patients with severe systemic inflammatory response syndrome. J Trauma. 2006 Sep;61(3):616-23; discussion 623. doi: 10.1097/01.ta.0000238228.67894.d7.
- Nickel RS, Osunkwo I, Garrett A, Robertson J, Archer DR, Promislow DE, Horan JT, Hendrickson JE, Kean LS. Immune parameter analysis of children with sickle cell disease on hydroxycarbamide or chronic transfusion therapy. Br J Haematol. 2015 May;169(4):574-83. doi: 10.1111/bjh.13326. Epub 2015 Mar 5.
- Pathare A, Al Kindi S, Alnaqdy AA, Daar S, Knox-Macaulay H, Dennison D. Cytokine profile of sickle cell disease in Oman. Am J Hematol. 2004 Dec;77(4):323-8. doi: 10.1002/ajh.20196.
- Purohit S, Alvarez O, O'Brien R, Andreansky S. Durable immune response to inactivated H1N1 vaccine is less likely in children with sickle cell anemia receiving chronic transfusions. Pediatr Blood Cancer. 2012 Dec 15;59(7):1280-3. doi: 10.1002/pbc.24206. Epub 2012 May 24.
- Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Wang WC. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst Rev. 2017 Jan 17;1(1):CD003146. doi: 10.1002/14651858.CD003146.pub3.
- Yazdanbakhsh K. Mechanisms of sickle cell alloimmunization. Transfus Clin Biol. 2015 Aug;22(3):178-81. doi: 10.1016/j.tracli.2015.05.005. Epub 2015 Jun 6.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CHUB-HO1 sickle cell
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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