Page 1150 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immune Reconstitution Therapy for

Immunodeficiency

Luigi D. Notarangelo, Sung-Yun Pai

Following the discovery of the major human leukocyte antigens or T cell–depleted) and the weight of the recipient. Blood
(HLAs) in 1958, hematopoietic stem cell transplantation (HSCT) group matching for ABO antigens is not required for HSCT, as
came into practice to provide treatment for a variety of congenital mature red blood cells (RBCs) or anti-ABO antibodies can be
and acquired disorders. Cure of an infant with severe combined removed by RBC depletion and plasma depletion, respectively.
immunodeficiency (SCID) in 1968 was the first successful experi- In the case of HLA-identical transplantation, marrow stem cells
ence in HSCT, marking the beginning of a new era in medicine. are then injected intravenously without further manipulation
Shortly thereafter, partial success was achieved also with HSCT into a central line in the recipient. In the case of mismatched
in a child with Wiskott-Aldrich syndrome (WAS). transplantation, bone marrow cells are usually T cell depleted in
For many years, the successful use of HSCT in severe vitro (see below); stem cells are then enumerated and injected
primary immune deficiency (PID) was largely restricted intravenously. More recently, injection of unmanipulated
to transplantation from HLA-matched related donors (MRDs), bone marrow cells from MMRD, followed by in vivo admin-
as HSCT from mismatched related family donors (MMRDs), istration of cyclophosphamide to prevent GvHD, has been
usually represented by haploidentical parents, was followed also used. 3
by severe complications, graft-versus-host disease (GvHD) in HSCs can also be retrieved from peripheral blood, following
particular. In the late 1970s, it was demonstrated in animal in vivo administration of granulocyte–colony-stimulating factor
models that removal of mature T lymphocytes from the graft (G-CSF) to the donor, usually at the dosage of 10 µg/kg/day for
obtained from mismatched marrow allowed successful reconstitu- 5 days, which allows mobilization of stem cells. In this case, stem
tion upon injection into lethally irradiated recipient animals. cells can also be purified by positive selection (see below), enumer-
This important achievement opened the way to a broader use ated, and injected.
of HSCT in severe forms of PID. More recently, transplantation Finally, UCB is another rich source of HSCs. At birth, cord
of hematopoietic stem cells (HSCs) from volunteer matched blood is collected in a heparinized medium and stored in liquid
unrelated donors (MUDs) and of umbilical cord blood (UCB) nitrogen, with small aliquots preserved for HLA typing. Whenever
has been increasingly used in individuals with PID. Overall, since sufficient compatibility is identified between a patient and stored
1968, over 2000 transplantations have been performed in patients cord blood, the latter is thawed and injected into the recipient
1,2
with PID, most of them in children with SCID. The increasing without further manipulation. With this procedure, the number
number of transplantations over the years reflects an increased of HSCs that can be transplanted is dictated by their concentration
awareness of PID, the broader availability of diagnostic in the cord blood sample and by the volume of the sample itself.
tools (including newborn screening for SCID), improved out- More recently, in vitro expansion of cord blood stem cells, and
comes as a result of advances in supportive and critical care transplantations with multiple cord blood units, have been
before and after HSCT, increasingly improved strategies to prevent attempted to overcome this limitation.
GvHD, and the greater availability of MUD and UCB for
transplantation. Donor Selection and Manipulation of the Graft
HSCT From a Related HLA-Identical Donor
HEMATOPOIETIC STEM CELL TRANSPLANTATION: The use of unfractionated stem cells from an HLA-identical
GENERAL CONSIDERATIONS sibling offers the best chance of rapid engraftment and immune
Sources of Hematopoietic Stem Cells reconstitution. In such cases, the HLA-identity between recipient
and donor minimizes the risk of GvHD. Furthermore, the mature
for Transplantation T cells contained in the graft provide a first line of immune
Several sources of HSCs are available for transplantation (Table reconstitution after transplantation, as they may expand and
82.1). HSCs can be retrieved from bone marrow, peripheral blood, lead to a rapid increase in the number of circulating T lympho-
or UCB (Chapter 2). Bone marrow stem cells are most commonly cytes as early as 2 weeks after HSCT. Engraftment of these mature
obtained by multiple aspirations along the iliac crests, usually T cells transplanted with the bone marrow of an MRD is par-
while the donor is under general anesthesia. The volume of bone ticularly important in infants with SCID, as it is early evidence
marrow that is obtained may vary between 500 mL and 1 L or of immune reconstitution in a severely immunocompromised
even more, depending on the type of transplant (HLA-identical host.

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