Page 1151 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1116 Part NINE Transplantation

TABLE 82.1 Sources of Hematopoietic GvHD. Several methods are available to attain T-cell
Stem Cells for transplantation depletion.
In the past, the method of soybean lectin agglutination and
Hematopoietic Stem Cell transplantation (HSCt) From a E-rosetting was frequently used. With this method, soybean lectin
related Donor allowed agglutination of the majority of mature marrow cells,
Bone marrow from a human leukocyte antigen (HLA)–genotypically which were removed by sedimentation. Further depletion of T
identical sibling
Bone marrow from an HLA-phenotypically identical family member lymphocytes was achieved by rosetting with sheep erythrocytes
Bone marrow from a haploidentical parent (E-rosetting technique) and density gradient centrifugation.
T cell depleted by negative selection with soybean lectin Importantly, T-cell depletion by soybean lectin agglutination
agglutination and rosetting with sheep red blood cells and E-rosetting maintains all immature marrow cells in the final
(E-rosetting) preparation.
T cell depleted by negative selection with monoclonal antibodies T-cell depletion can also be achieved by incubation of bone
Positive selection of CD34 cells
+
marrow with monoclonal antibodies (mAbs) to T lymphocytes
HSCt From a Matched Unrelated Donor plus complement. Campath-1 G, Leu 1, and other mAbs have
Unmanipulated bone marrow been used for this purpose, but the degree of T-cell depletion
+
T cell–depleted bone marrow by means of positive selection of CD34 that is achieved with these agents is less effective than with the
cells soybean lectin and E-rosetting, and therefore a higher incidence
+
Positively selected peripheral blood CD34 cells of GvHD has been reported. More recently, use of mAbs directed
against the αβ form of the T-cell receptor (TCR) and against
HSCt From an Unmanipulated related or Unrelated CD19 has entered clinical practice, with excellent results. 4
Cord Blood
However, the most common method to obtain transplantable
+
HSCs is represented by positive selection of CD34 cells using
mAbs. This method allows very robust depletion of mature T
−
KEY CONCEPtS cells; however, it also removes immature CD34 cells and other
Sources of Stem Cells and Selection of Donors cells (especially stromal marrow cells) that can facilitate stem
cell engraftment.
for Hematopoietic Stem Cell Transplantation in Selection of the best donor is another important aspect of T
Primary Immunodeficiencies cell–depleted haploidentical HSCT for SCID. In general, the
donor is represented by one of the parents, since the volume of
Sources of hematopoietic stem cells (HSCs) for transplantation include
bone marrow, peripheral blood, and cord blood. bone marrow that can be collected is much higher than it would
If the donor is a genotypically human leukocyte antigen (HLA)–identical be if a haploidentical sibling were to serve as donor. Maternal
sibling, unmanipulated bone marrow is used as source of stem cells. T-cell engraftment in utero is a common finding in infants with
Whenever the donor is HLA-mismatched to the recipient, T-cell depletion SCID and has been observed in almost 40% of patients with
must be performed to eliminate mature T lymphocytes from the graft. SCID. In such cases, T cell–depleted HSCT should be performed
Methods for T-cell depletion of the bone marrow include use of soybean using the mother as donor, if possible, since transplantation
lectin agglutination and E-rosetting, depletion with monoclonal antibodies from the father might cause a graft-versus-graft reaction.
(mAbs), and positive selection of stem cells.
Cord blood is a rich source of stem cells. However, the volume of cord In Utero Haploidentical HSCT
blood is limited, so its use is mainly restricted to young patients.
The number of volunteers included in Bone Marrow Donor Registries is The identification of a growing number of immunodeficiency-
expanding. Consequently, there is a continuous increase in the number causing genes has resulted in continuous improvement in prenatal
of matched unrelated donor (MUD) transplantations performed for diagnosis, which, in most cases of severe immunodeficiency, can
patients with primary immunodeficiencies. now be accomplished on chorionic villi DNA at 10–11 weeks
Whenever cord blood or MUD stem cells are used, conditioning regimen
must be given to the recipient before transplantation to facilitate of gestation. This has prompted prenatal transplantation of
+
engraftment of donor stem cells. parental positively selected CD34 stem cells into the peritoneum
Therapeutic options for patients with severe combined immunodeficiency of fetuses prenatally diagnosed with SCID, under ultrasound
(SCID) and other severe forms of primary immunodeficiency (PID) guidance.
include transplantation from HLA-genotypically identical donor, mis- The rationale underlying in utero HSCT is based on a
matched related donors (MMRD), and MUDs.
lower risk of graft rejection resulting from decreased fetal
immunocompetence (although this consideration is not relevant
in the case of fetuses with SCID), a presumed induction of
HSCT From a Haploidentical Donor tolerance to paternal antigens (which might favor successful
Unfortunately, the option of related HLA-identical HSCT is engraftment after postnatal transplantation from the same donor),
limited only to a minority of patients. When no such donor is the predicted competition between donor and autologous stem
available, stem cell transplantation from a haploidentical parent cells at a time when several empty niches should be available
should be considered, particularly in infants with SCID. for stem cell engraftment, the potential ability to provide preemp-
The rationale for haploidentical HSCT is based on the ability tive treatment (thus reducing the risk of postnatal infection),
of donor-derived stem cells to repopulate the recipient’s vestigial and the lower cost of the procedure that does not require pro-
thymus and give rise to fully mature T lymphocytes. Indeed, longed hospitalization. However, in utero HSCT is associated
this is a life-saving procedure that has been successfully applied with the potential risks of fetal loss and of GvHD. Finally, if
to several hundreds of infants with SCID. 1,2 maternal T cells had engrafted into the fetus with SCID, trans-
+
However, this procedure requires careful removal of T lym- plantation of paternal CD34 cells might cause graft-versus-graft
phocytes from the graft, as these would otherwise cause severe reaction.