Page 1157 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1122 Part NINE Transplantation

HSCT is associated with a higher risk of late infections. In a Finally, prolonged nutritional support has been reported after
single-center study of 90 patients with SCID treated with HSCT, HSCT for SCID. This complication is more frequent among
11 (12%) developed significant infectious complications 2–17 patients treated by mismatched related or unrelated donor HSCT,
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years after transplantation. Among late infections, chronic skin especially if cGvHD, immune dysregulation, and poor immune
warts caused by papilloma virus have been observed in a sig- reconstitution are also present. Infants with Artemis deficiency
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nificant fraction of infants with γc or JAK3 deficiency after HSCT. (leading to impaired DNA repair) are at particularly high risk
This complication may occur also in patients who attain robust for late complications, including growth retardation, requirement
immune function and probably results from signaling defects for nutritional support, and dental abnormalities. 16,19
that involve extrahematopoietic cells, such as keratinocytes.
GvHD is another major complication of HSCT for SCID. In Quality and Kinetics of T-Cell Immune Reconstitution
a series of 240 patients with SCID who received HSCT in North The effectiveness of HSCT in SCID is well illustrated by the
America between 2000 and 2009, the cumulative incidence of normalization of the number and function of T lymphocytes that
aGvHD of grade 2–4 at 100 days after transplant was 20%, with is achieved after transplantation (Figs. 82.4 and 82.5). The efficacy
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no significant difference based on donor type. By contrast, in of the procedure has been demonstrated in all forms of SCID,
their article describing the experiences of HSCT for SCID at although the T-lymphocyte count after HSCT tends to be lower
two centers (Brescia, Italy; and Toronto, Canada), Grunebaum in patients with adenosine deaminase (ADA) deficiency, possibly
et al. reported that aGvHD developed in four (31%) of 13 patients reflecting irreversible thymic damage. Moreover, normalization
who received related HLA-identical HSCT, 18 (45%) of 40 patients of T-lymphocyte count after HSCT demonstrates the ability of
treated with T cell–depleted haploidentical transplantation, and stem cells to seed and differentiate in a vestigial thymus.
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30 (73%) of 41 patients receiving MUD HSCT. Buckley et al. The kinetics of T-lymphocyte reconstitution differs substan-
reported that GvHD occurred in 45 (30.2%) of 149 patients tially, depending on the type of transplant. The unmanipulated
given T cell–depleted mismatched parental bone marrow, eight graft from a related HLA-identical donor contains mature T
(47%) of 17 patients given unfractionated HLA-identical marrow, lymphocytes. Homeostatic as well as antigen-driven expansion
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and four (80%) of five patients given placental blood. In most of these mature T cells occurs as early as 2 weeks after transplanta-
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cases, GvHD occurred when there was presence of transplacentally tion (Fig. 82.6). These T cells have a memory (CD45RO)
acquired T lymphocytes. In most cases in this study, the GvHD phenotype, are fully competent, and, in fact, provide the recipient
observed was mild (grade I or II) and required no treatment; with functional immunity.
however, 11 patients developed GvHD grade III or IV and required Mature T cells are present also in bone marrow grafts collected
treatment with steroids, cyclosporine, and/or tacrolimus. None from MUDs. However, the use of conditioning in MUD HSCT
of these patients has died since then, but one has developed impairs, at least in part, immune development in such transplants,
cGvHD. Although continuous improvement in HLA typing has compared with unconditioned HSCT from related HLA-identical
resulted in a progressively lower incidence of aGvHD in the last donors (see Fig. 82.6).
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decades, these data illustrate the need for careful monitoring of In contrast, newly generated, naïve (CD45RA CD31 ) T
infants treated with other than related HLA-identical HSCT and lymphocytes do not appear in circulation until 3–6 months after
call for adherence to guidelines on the use of immunosuppression HSCT, irrespective of the type of transplant (HLA-identical or
for GvHD prophylaxis after MUD HSCT or after conditioned mismatched), and their number tends to peak at approximately
T cell–depleted haploidentical transplantation. 1 year after HSCT, when a fully polyclonal T-cell repertoire is
Chronic GvHD disease has been reported in 10 (11%) of 90 usually observed. These naïve T lymphocytes are the product of
patients who have survived for at least 2 years after receiving ongoing active thymopoiesis, as shown by the fact that they
HSCT for SCID in Paris. Six of them developed disseminated contain T-cell receptor excision circles (TRECs). TRECs are
cGvHD, and three died of cGvHD and related infectious complica- extrachromosomal DNA episomes, which are generated during
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tions. A similar rate of cGvHD (15% at 2 years post-HSCT) V(D)J recombination (Chapter 4) and are not duplicated during
has been observed in the North American series of 240 infants mitosis. Therefore TRECs identify newly generated naïve T
with SCID. 2 lymphocytes, and their enumeration in peripheral blood is used
Immune dysregulation and autoimmunity represent additional as a method to identify babies with SCID at birth. 20
complications of HSCT for SCID. In a joint series of 94 infants The kinetics of T-cell reconstitution is influenced by the
with SCID who received transplantations in Brescia (Italy) and recipient’s age. Transplantations performed early in life (at <3.5
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Toronto (Canada), we have reported that six of 41 patients who months of age) lead to superior thymic output. This may reflect
received MUD HSCT, and five of 40 children treated with T lack of thymic damage (which is often observed in older infants
cell–depleted haploidentical transplantation developed auto- after infections); alternatively, it is possible that a younger thymus
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immune cytopenias. These complications may develop a few has intrinsic superior ability to support active thymopoiesis.
months after HSCT (when skewing of the T-cell repertoire may Quantitation of TRECs sequentially after HSCT is an accepted
be observed) or may persist, particularly in infants with delayed approach to assess engraftment of bona fide stem cells and to
and incomplete immune reconstitution. In particular, Neven monitor persistence of immunity. Although an earlier study had
et al. have reported that among 90 long-term survivors after shown that levels of TRECs tended to decline at 10 years after
HSCT for SCID, 12 patients suffered from autoimmune and HSCT in recipients of unconditioned mismatched-related
inflammatory complications at more than 2 years after HSCT transplants, more recent observations from the same group
for SCID, and in six of them, the onset of such complications indicate that robust thymopoiesis and generation of a diversified
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was within the first 2 years after transplantation. These late repertoire of T lymphocytes were maintained over the long term
manifestations of immune dysregulation are often associated after HSCT. 21
with incomplete immune reconstitution and may lead to a poor Vigor of immune reconstitution at >2 years after HSCT is
outcome. influenced by the donor type, use of conditioning, and SCID