Mechanisms of Immune Deficiency

Immune Deficiency Clinical Trial

Official title:

Mechanisms of Immune Deficiency

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03707782
• Other study ID #: 18-0337
• Status: Recruiting
• Start date: October 20, 2020
• Est. completion date: December 2023

Study information

• Verified date: April 2022
• Source: University of Colorado, Denver
• Contact: Charles Kirkpatrick
• Phone: (303) 724-7197
• Email: charles.kirkpatrick[@]ucdenver.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

1. The purpose of this study is to learn more about the changes in genes, cells and proteins that cause immune deficiency diseases. 2. The early stages of the study will focus on two groups of patients: 1. members of families in which several persons have symptoms or medical histories that suggest immune deficiency. 2. Patients who have received treatments with medications or drugs that affect functions of the immune system (secondary immune deficiencies). It is hoped that studies will provide guidelines for extension of the research to other patient groups. Up to 200 patients and family members will be invited to participate.

Description:

The experiments that are proposed in this portion of the study are intended to: 1. characterize the significance of the variant form of EZH2 identified in this family. They will characterize the degree of methylation of lysine 27 of histone H3 in subjects with the variant and members of the same family who have the wild type gene. The functional methyltransferase activity of the variant and wild type genes will be measured. 2. characterize the current status of B-cell maturation and function in subjects with either the variant gene and the wild type gene. 3. characterize B-cell function (antibody production) and the quality of antibody produced after immunizations in subjects with the wild type gene or the variant gene.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

1. Immunodeficiency disease; or

2. family member of individual with immunodeficiency disease

Exclusion Criteria:

1. Persons with immune deficiencies that are secondary to other diseases such as malignancies.

2. Persons who do not have immune deficiencies, persons who are not meet eligibility criteria

Related Conditions & MeSH terms

• Immune Deficiency
• Immunologic Deficiency Syndromes

Locations

Country	Name	City	State
United States	UColorado	Denver	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Denver	Colorado Clinical & Translational Sciences Institute

Country where clinical trial is conducted

United States, 

References & Publications (5)

Bödör C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, Marzec J, Araf S, Wang J, Lee AM, Clear A, Montoto S, Matthews J, Iqbal S, Rajnai H, Rosenwald A, Ott G, Campo E, Rimsza LM, Smeland EB, Chan WC, Braziel RM, Staudt LM, Wright G, Lister TA, Elemento O, Hills R, Gribben JG, Chelala C, Matolcsy A, Kohlmann A, Haferlach T, Gascoyne RD, Fitzgibbon J. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013 Oct 31;122(18):3165-8. doi: 10.1182/blood-2013-04-496893. Epub 2013 Sep 19. — View Citation

Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78. doi: 10.1016/j.jaci.2015.04.049. Epub 2015 Sep 12. — View Citation

Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, Ponzoni M, Testa G, Nojima T, Doglioni C, Kitamura D, Toellner KM, Su IH, Casola S. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013 Dec;123(12):5009-22. doi: 10.1172/JCI70626. Epub 2013 Nov 8. Erratum in: J Clin Invest. 2014 Apr 1;124(4):1869. — View Citation

O'Meara MM, Simon JA. Inner workings and regulatory inputs that control Polycomb repressive complex 2. Chromosoma. 2012 Jun;121(3):221-34. doi: 10.1007/s00412-012-0361-1. Epub 2012 Feb 19. Review. — View Citation

Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003 Feb;4(2):124-31. Epub 2002 Dec 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of Serum immune globulin	The clinical definition of "hypogamma-globulinemia is values that are 2 SD below the mean value for the testing laboratory. For this study values that are below the lower limit of abnormal will be scored as abnormal. Chi-square analysis or Fisher's exact test will compare values between subjects with the wild type gene and the variant gene.	each year for up to 20 years
Primary	Antibody responses	A four-fold difference or a post-immunization titer of =1.3 µg/ml is scored as a true antibody response. Antibody titers and avidity indices are transformed to log2 and evaluated using the Student's T-test.	4 weeks
Primary	Measurement of NK cell function	Spearman correlation will be used to compare the relationship between expression of CD207a by NK cells that are activated with K562 cells or NK cells that are activated with PMA/iono.	one time
Primary	DNA sequencing	When indicated, whole exome or whole genome sequencing will be done to identify genetic basis (if any) of the immune deficiency	one time
Primary	measurement of cellular components of the immune system	Flow cytometry will be used to identify numbers of cells of various types (e.g.,subpopulations of B-cells and T-cells) to evaluate changes in various cell populations over time. This is especially important for studies of family members who carry disease-causing or disease-associated genes but are clinically health at the time of the first study	each year for up to 20 years
Primary	health outcome measurements	The SF-36 form will be used serially to identify changes in health over time	each year for up to 20 years
Primary	Measurement of avidity	avidity indices are transformed to log2 and evaluated using the Student's T-test	each year for up to 20 years