Severe Immunodeficiencies: BMT or Gene Therapy?

Introduction

Immune deficiencies occur infrequently in the immune system, but when they do, they are generally associated with severe manifestations owing to the lack of protections from life-threatening infections. As most are linked to a genetic defect, they are present at birth. A timely and correct diagnosis is of critical importance since routine vaccinations of these infants with attenuated but viable vaccinal strains may have dire consequences, including poliomyelitis, polioencephalitis, giant cell pneumonia (measles vaccine), or fatal progressive vaccinia. Still, a majority of cases are diagnosed only around the sixth or seventh month of life, when infective complications may have already severely compromised the very young patients.^[1]

Boys are at a higher risk than girls, with a sex ratio of 3:1 owing to the relatively higher incidence within this group of X-linked syndromes. Conventional treatment is based on transplantation of HLA-identical bone marrow from siblings, HLA-haploidentical bone marrow from family members, or HLA-matched unrelated donors.

Immune deficiencies are generally classified depending on the arm of the immune system that is impaired. Accordingly, there are T-cell immunodeficiencies, B-cell immunodeficiencies, combined immunodeficiencies in which both T and B compartments are compromised (eg, X-linked severe combined immunodeficiency [SCID-X]), and other cases involving defects in phagocytic cells (eg, leukocyte adhesion deficiency [LAD]) and/or natural killer (NK) cells ( Table 1 ).^[1,2]

According to the molecular defect,^[2,3] T-cell immunodeficiency syndromes can be divided into 4 main groups. A defective adenosine deaminase (ADA) enzyme, involved in purine phosphorylation, leads to apoptosis in precursor T cells by deoxynucleotides; a defective RAG1/2 gene, involved in T-cell receptor (TCR) and B-cell receptor (BCR) rearrangement, leads to generation of abnormal T and B cells; defects in the TCR-associated complex CD3, in the surface molecule CD45, and in ZAP70 all contribute to expansion of defective T-cell precursors.

In addition, abnormalities in the gamma chain, in the IL-7 receptor alpha, and in JAK3 kinase all contribute to defective signaling of gamma-chain dependent cytokines that include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21.^[1] The outcome is a nonfunctional or only partially functional immune system that cannot rely on the generation, activation, and expansion of sufficient numbers of normal T, B, and/or NK cells ( Table 2 ).

Cite this: Severe Immunodeficiencies: Bone Marrow Transplantation or Gene Therapy? - Medscape - Jun 03, 2003.

Table 1. Classification of Human Immunodeficiencies
Compartment Affected	Disease/Syndrome	Defect
Combined T-, B-, and/or NK-cell immunodeficiency	SCID	RAG1, RAG2, Artemis, or CD45 deficiency; reticular dysgenesis; Native American SCID
	X-linked SCID	Gamma chain deficiency or Jak3 deficiency
	Deficiencies of purine metabolism	Adenosine deaminase deficiency; purine nucleoside phosphorylase deficiency
	MHC Class II deficiency	CIITA, RFX-5, RXAP, or RFXANK deficiency
	MHC Class I deficiency
	Hyper IgM syndrome	CD40, CD40L, or Nemo deficiency; non-X linked SCID
	CD3 deficiency	CD3-epsilon or CD3-gamma deficiency
	Zap 70 deficiency
	IL-2 receptor alpha chain
	CD8-alpha deficiency
Predominantly affecting antibody production	Agammaglobulinemia	X-linked (XLA), XLA with GH deficiency; BLNK, Ig-alpha, mu-chain, or lambda-5 deficiency
	Kappa chain deficiency
	Selective deficiency of a subclass	Gamma-1, gamma-2, gamma-3, gamma-4, alpha-1, alpha-2, or epsilon deficiency
	Common variable immunodeficiency
	IgA deficiency
	Transient hypogammaglobulinemia of infancy
Defects in lymphocyte apoptosis	Autoimmune lymphoproliferative syndrome	Defects in CD95/Fas/APO receptor or ligand
Other syndromes	Wiskott Aldrich syndrome
	Duncan disease
	Di George anomaly
	Hyper IgE recurrent infection syndrome
Defects of phagocyte function	Chronic granolumatous disease	X-linked; p22/phox or p47/phox deficiency
	Leukocyte adhesion defects	LAD or LAD 2
	Myeloperoxidase deficiency
	Cyclic neutropenia
Interferon-gamma immunodeficiencies	Interferon-gamma1 deficiency	Interferon-gamma 1, gamma 2, IL-12/p40 or beta 1 deficiency
DNA breakage syndromes	Ataxia teleangectasia
	Bloom syndrome
	Nijmegen-breakage syndrome
Defects of complement cascade	C1, 2, 3, 4, 5, 6, 7, 8, or 9 deficiency
	Factor B deficiency
Defects of complement regulatory proteins	Hereditary angioedema
	C-4 binding protein deficiency
	Factor D, I, or H1 deficiency
	Properdin factor C deficiency
	CD55 or CD59 deficiency

Table 2. Frequency of Defects in SCIDs
Immunodeficiency	Defective	Frequency
T- B- NK-	Gamma chain	46.2%
T- B- NK-	Jak3	6.5%
T- B+ NK+	IL-7 receptor alfa	9.5%
T- B- NK-	ADA	16.6%
T- B- NK+	RAG1/2	3.0%
T- B- NK+	Artemis	1.2%
	Unknown	6.5%

Table 3. Survival in SCID Children Following BMT (Duke Series)
SCID type	Survival
X-linked	79%
Jak3 deficiency	88%
ADA deficiency	77%
IL-7-R alfa deficiency	69%
RAG1/2 deficiency	75%

Table 4. Characteristics of Gamma Chain Retrovirally Transduced T Cells
- Normal counts and normal subset distribution
- Normal V-beta repertoire
- Normal phenotype (CD45RA+ naive and CD45RO+ memory T cells)
- Presence of recent thymic emigrants (TREC+) with thymopoiesis continuing 4 years after gene therapy
- Normal functions
- Approximately 1 copy of provirus/T cell

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Severe Immunodeficiencies: Bone Marrow Transplantation or Gene Therapy?

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