Page 1152 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 82 Immune Reconstitution Therapy for Immunodeficiency 1117

In a series of five in utero HSCT performed at the University recipient’s cells. Furthermore, conditioning regimens can cause
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of Brescia, Italy, all three cases with B SCID survived, with toxicity of several organs. Myeloablative regimens cause anemia,
evidence of T-cell reconstitution. However, transient or no thrombocytopenia, and leukopenia. Consequently, supportive
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immune reconstitution was observed in two fetuses with B SCID. treatment with RBC and platelet transfusions is necessary during
The use of in utero HSCT for SCID is now largely unjustified, the aplastic phase. Finally, the leukopenia predisposes the patient
also in consideration of the fact that newborn screening allows to an increased risk of life-threatening bacterial or fungal
rapid identification of infants with SCID and permits rapid infections.
referral to HSCT, with long-term survival that exceeds 90%. 5 The frequency and severity of these complications depend
on the type of transplant, the possible use of a conditioning
HSCT From Matched Unrelated Donors regimen, and specific considerations related to the underlying
Since the first successful HSCT performed in 1977 in an infant disorder and to the clinical status of the recipient before
with SCID, HSCT from MUD has been increasingly used to transplantation.
treat severe PID. MUD HSCT has been shown to be more effective
than T cell–depleted HSCT in patients with immunodeficiencies KEY CONCEPtS
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other than SCID, and it has been successfully used also in infants Rejection of Donor Stem Cells by the Host
with SCID. 6 Immune System and Reaction of Donor’s T
Transplantation from MUD has been facilitated by the increas-
ing number of volunteer donors included in registries worldwide. Lymphocytes to the Host
In addition, advances in the quality of the techniques used for The host T cells are responsible for the elimination of donor stem cells,
HLA typing permits this identification of an optimal MUD and regardless of the degree of human leukocyte antigen (HLA) compatibility.
reduction in the risk of GvHD. As of April 2016, more than 28 Under these circumstances, other than in patients with severe combined
million donor volunteers and UCB units were included in the immunodeficiency (SCID), a chemotherapy-based conditioning regimen
Bone Marrow Donors Worldwide (BMDW) registry. At present, must be used before transplantation to allow for donor stem cell
engraftment.
it takes only a few weeks to identify a MUD. However, the prob- If T cells are present in the graft, and especially if there is HLA-
ability of finding a suitable donor is lower for selected ethnic or incompatibility between the donor and the recipient, the donor’s T
racial groups that are poorly represented among volunteer donors. lymphocytes may react to host alloantigens and cause graft-versus-host
Importantly, MUD HSCT requires use of a preparative disease (GvHD).
chemotherapy regimen in the recipient (even in the case of SCID) Risk factors for GvHD include HLA-mismatch between donor and recipient,
and GvHD prophylaxis (because of likely disparity between donor older age at transplantation, gender mismatch, and previous viral
and recipient at minor histocompatibility loci), whereas neither infections.
one is necessary for related HLA-identical HSCT in SCID infants. GvHD may develop early after transplantation (acute GvHD), or at 100
days or more after transplant (chronic GvHD). GvHD is one of the
major causes of death and long-term disability after stem cell
HSCT Using Unmanipulated Cord Blood transplantation.
As opposed to MUD HSCT, which requires identification, Prevention is the best approach to the management of GvHD. Prevention
willingness, and medical clearance of an adult volunteer, stored of GvHD is based on selection of optimal donor and vigorous T-cell
cord blood is readily available as a source of stem cells for depletion in the case of HLA mismatch between the donor and the
transplantation. In addition, the risk of GvHD at any given degree recipient. Immunosuppressive drugs, such as cyclosporine, are another
potent form of GvHD prevention.
of HLA matching is lower when using cord blood compared
with MUD HSCT so that greater HLA disparity with the recipient
can be tolerated. However, the number of cells contained in any
defined unit is still a major limitation of cord blood. Low Graft Rejection
cell dose is not usually a problem for transplants performed in Graft rejection reflects the presence of immunocompetent cells
infants with SCID or other severe forms of immune deficiency in the host that specifically recognize and react to donor-derived
because of the low weight of the recipient. Indeed, unrelated stem cells. Several factors influence the likelihood of graft rejec-
umbilical cord stem cell transplantation has been successfully tion, in particular (i) the degree of immunocompetence of the
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used in dozens of patients with severe PID. In practice, an host; (ii) the degree of HLA disparity between donor and recipient;
unrelated HSC donor should be simultaneously searched for in (iii) the number and source of stem cells infused; (iv) the type
cord blood banks and in bone marrow donor registries for patients of conditioning regimen used; and (v) the possible presensitization
lacking an HLA-identical sibling HSC donor. The option of of the host to donor histocompatibility antigens.
performing cord blood transplants should be based on urgency In the case of infants with SCID, graft rejection is an unlikely
of the transplantation, the cell dose required, and the number event because of the virtual lack of T cells that characterizes
of HLA disparities. these conditions. However, natural killer (NK) cells are present
As for HSCT from MUD, transplantation using cord blood in several forms of SCID and may contribute to graft rejection.
usually requires pretransplantation conditioning and GvHD Indeed, among infants with SCID who received HSCT without
prophylaxis, irrespective of the underlying disease. conditioning chemotherapy, reduced overall survival and increased
requirement of additional procedures have been observed in
Complications of Hematopoietic Stem those with NK SCID compared with NK SCID (Fig. 82.1). In
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Cell Transplantation other forms of PID, there is sufficient immune function in the
A variety of complications can compromise the success of HSCT. host to allow for rejection of donor-derived stem cells, unless
Among these, incompatibility between donor and recipient can an appropriate conditioning regimen is used before HSCT.
lead to graft rejection by the host immune system or to GvHD In children with nonmalignant disease, the most commonly
caused by alloreactivity of donor-derived lymphocytes to the used myeloablative conditioning regimen consists of busulfan