Apheresis of Patients With Immunodeficiency

Background:

Primary immunodeficiency diseases (PID) represent candidate genetic disorders for new therapeutic approaches. Our laboratory is developing new therapies for individuals with PID using autologous CD34+ hematopoietic stem cells (HSC). Newer therapies may circumvent problems with allogeneic HSC transplantation, especially graft rejection and graft-versus-host-disease. We are particularly interested in three PID: Dedicator of CytoKinesis-8 (DOCK8) deficiency, Leukocyte Adhesion Deficiency type 1 (LAD-1), and GATA2 Deficiency. For all three diseases the gene has been cloned. Testing new therapies for these diseases would be considerably enhanced by the acquisition of peripheral blood CD34+ cells from individuals with these immunodeficiency diseases.

Objectives:

To provide a source of filgrastim or filgrastim biosimilar mobilized peripheral blood CD34+ hematopoietic stem cells (HSC) for laboratory research studies for DOCK8 deficiency, LAD-1, and GATA2 Deficiency.

Eligibility:

Individuals 18-40 years old with DOCK8 deficiency, LAD-1, and GATA2 Deficiency who meet the eligibility requirements will be considered for this protocol.

Design:

Individuals 18-40 years old with DOCK8 deficiency, LAD-1, and GATA2 Deficiency will receive five days of filgrastim or filgrastim biosimilar followed by a single apheresis. CD34+ cells will be selected and frozen in aliquots by the Cell Processing Section of the Department of Transfusion Medicine. No treatments, or investigational therapy will be administered on this protocol.

-INCLUSION CRITERIA - PATIENT:

• Individuals age 18-40 years.
• Diagnosis of DOCK8 deficiency, LAD-1, or GATA2 Deficiency:

-DOCK8 deficiency

• Homozygous or compound heterozygous mutations in the DOCK8 gene.

-LAD-1

• Less than 10% CD18 expression on the neutrophil surface.

-GATA2 Deficiency

• Deleterious mutation of GATA2 Gene
• Serum creatinine <1.5 mg/dL.
• Total Bilirubin < 3mg/dl, ALT and AST < 5X upper limit of normal.
• Ability to give informed consent.
• Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
• Individuals of childbearing age must have a negative urine pregnancy test within one week prior to beginning filgrastim or filgrastim biosimilar administration.

Exclusion criteria

- PATIENT:

• HIV infection.
• Chronic hepatitis B or hepatitis C virus infection.
• History of psychiatric disorder which may compromise compliance with protocol, or which does not allow for appropriate informed consent.
• Active infection that is not responding to antimicrobial therapy.
• Pregnant Individuals may not participate per OHSRP SOP.
• Any Individual who is breastfeeding as the effects of filgrastim or filgrastim biosimilar product on infants is not known.
• Sexually active individuals capable of becoming pregnant who are unable or unwilling to use effective form(s) of contraception during the 10 days surrounding filgrastim or filgrastim biosimilar product administration and apheresis procedure(s). Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner s vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence. Males on the protocol must use an effective form of contraception at study entry.
• Presence of active malignancy in another organ system other than the hematopoietic system.
• Individuals with active pulmonary disease.
• History of hypertension that is not controlled by medication, stroke, or severe heart disease. Individuals with symptomatic angina will be considered to have severe heart disease and will not be eligible.
• Other medical contraindications to stem cell donation (i.e., severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident).
• Thrombocytopenia (platelets less than 50,000 per microliter) at baseline evaluation.
• Individuals receiving experimental therapy or investigational agents.
• Sensitivity to filgrastim, to E. Coli derived products, or to a biosimilar recombinant protein to filgrastim.
• Individuals must test negative for transfusion-transmissible infectious agents, including hepatitis B (HBsAg), hepatitis C (anti-HCV), HIV (anti-HIV-1/2).