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Chapter 106 Haploidentical Hematopoietic Cell Transplantation 1619

cells reactive against allogeneic HLA molecules. T cells recognize a
The Increasing Popularity of Human Leukocyte Antigen–
BOX 106.1 Haploidentical Donors complex determinant comprising specific amino acid residues of the
HLA molecule as well as amino acid residues of the bound peptide.
The number of human leukocyte antigen (HLA)-haploidentical stem It has been estimated that there are 50,000 to 100,000 copies of each
cell transplant procedures performed is increasing on a global scale. HLA molecule on a cell surface, with as many as 5000 different
China is the leader in HLA-haploidentical (“haplo”) stem cell trans- peptides being presented. Thus each allogeneic HLA molecule pro-
plants (SCTs) on a per-country basis, perhaps because the one-child vides as many as 5000 distinct recognition units corresponding to
policy there nullifies the availability of an HLA-matched sibling for many 5000 distinct alloreactive T cells. In contrast, a non-HLA or “minor”
patients. In the past 5 years, the number of haplo transplants performed histocompatibility antigen consists of a single allelic peptide presented
in Europe and the United States has more than doubled. Reports of by a single species of HLA molecule. Thus whereas the frequency of
successful haplo SCTs are appearing in the published literature from T cells reactive to a single minor histocompatibility antigen is on the
countries with more limited economic resources, such as Brazil, India,
and Romania. order of 1 in 50,000, the frequency of anti-HLA alloreactive T cells
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There are clinical, practical, and economic reasons for the increasing has been estimated to be on the order of 5% to 10%. The higher
popularity of HLA-haploidentical SCT. Clinically, results of the proce- frequency of T cells reactive to allogeneic HLA molecules than to
dure have improved dramatically over the past 10 to 15 years, to the minor histocompatibility antigens corresponds to a higher incidence
point that the outcomes of haplo SCT approach or equal those of of graft rejection and GVHD after HLA-haploidentical SCT than
HLA-matched sibling or unrelated donor transplantation (see “Integrat- after HLA-matched SCT. The second property of alloreactive T cells
ing HLA-Haploidentical SCT into Clinical Practice: Comparison of that contributes to a high incidence of graft failure and GVHD after
Outcomes With Other Graft Sources”). Absent these improvements, all haploSCT is a significant proportion of HLA-alloreactive memory T
other advantages of haplo donors would be meaningless. A major cells, even in donors and recipients who have not been exposed to
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practical advantage of the haplo option is donor availability. A haplo
donor can be found for nearly every patient referred for allogeneic SCT, allogeneic HLA molecules through pregnancy or blood transfusions.
because every biologic child or parent of a patient is HLA haploidenti- T cells that are immunized against environmental antigens, especially
cal, and each sibling or half-sibling has a 50% chance of being HLA viruses, can cross-react against allogeneic major histocompatibility
8,9
haploidentical. The likelihood of finding a haplo donor increases further complex (MHC) molecules. The phenomenon in which viral infec-
if one is willing to consider second-degree relatives, such as aunts, tion triggers cross-reactive memory against allogeneic HLA molecules
uncles, nieces, nephews, or cousins, as donors. The wide availability is termed heterologous immunity and may be a formidable barrier to
of haplo donors is especially important for members of ethnic minority the establishment of donor hematopoietic cell chimerism or the
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groups that are underrepresented in registries of volunteer unrelated induction of tolerance to transplanted organs. Unlike naive T cells,
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donors. Relatives, especially parents and children, tend to be highly which are sensitive to chemotherapy-induced apoptosis and to
motivated to donate and can do so more than once if needed to treat
graft failure or relapse. The treating center has greater control over the immunologic tolerance induction by antigen without costimula-
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timing of transplants when haplo donors than when unrelated donors tion, memory T cells are more resistant to chemotherapy-induced
are used. Clinical trials and advances in adoptive cellular therapy of death, can induce costimulatory signals on antigen-presenting cells
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cancer may be easier using related donors, because unrelated donor that they encounter, and are resistant to tolerance induction by
lymphocytes for infusion are regulated by the U.S. Food and Drug regulatory T cells (Tregs) 14,15 or to T cell–depleting antibodies. 16–18
Administration as a biologic. Thus an investigational new drug applica- The presence and substantial number of memory T cells reactive to
tion must be filed for any clinical trial employing the infusion of lym- allogeneic HLA molecules make control of graft rejection and GVHD
phocytes from unrelated donors, but not for minimally manipulated more challenging after HLA-haploidentical SCT than after HLA-
lymphocytes from related donors. matched SCT.
Finally, haplo stem cells are inexpensive compared with stem cells
from unrelated adult volunteers or from umbilical cord blood. This, B cells and NK cells also participate in the immune response to
combined with the growing availability of inexpensive methods of graft- HLA-mismatched tissues. Allogeneic HLA molecules can elicit the
versus-host disease prophylaxis for haplo SCT (especially posttransplant formation of alloantibody. Preexisting donor-specific antibodies
cyclophosphamide), makes the haplo option increasingly attractive in (DSA) against HLA molecules are a major risk factor for graft failure
countries with limited economic resources. In many countries, the after HLA-haploidentical SCT. Pregnancy and blood transfusions are
government allocates a fixed budget for allogeneic stem cell transplan- sensitizing events that can lead to the formation of antibodies against
tation. By lowering the total cost of the transplant for each patient, the HLA molecules. The prevalence of antidonor HLA antibodies in
haplo option permits more patients to receive this potentially lifesaving parous women has been reported to be as high as 42% ; such sensi-
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procedure.
tization is directed against unshared HLA molecules expressed by
their children. DSA can be detected by flow cytometric crossmatch
tests using beads coated with a single HLA or by complement-
dependent cytotoxicity (CDC) testing, in which the patient’s serum
patients lacking an HLA-matched sibling or URD (see Modern is mixed with donor lymphocytes in the presence of complement. In
Approaches to HLA-Haploidentical SCT section later). one study, a positive crossmatch for antidonor lymphocytotoxic
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antibody was associated with a 2.3-fold increased risk of graft failure.
IMMUNOLOGIC CONSIDERATIONS IN A positive crossmatch by CDC assay should be considered a contra-
indication to the use of the donor against whom the antibodies are
HLA-HAPLOIDENTICAL HSCT directed. Patients with DSA detectable by flow cytometric crossmatch
assay but not by CDC assay may be considered for a desensitization
The HLA class I and class II molecules play a central role in the protocol to reduce the level of antibody in the serum so as to allow
human immune response to infection and to transplanted tissues. engraftment of the transplanted cells, as discussed later.
The HLA class I molecules HLA-A, HLA-B, and HLA-C present
peptide antigens, generally 8–11 amino acids in length, for recogni-
+
tion by CD8 T cells. These molecules can also deliver stimulatory NK Cell Alloreactions After Allo-SCT
or inhibitory signals to natural killer (NK) cells. The HLA class II
molecules HLA-DRB1, HLA-DQB1, and HLA-DPB1 present NK cells may play a significant role in inducing GVL effects after
peptide antigens, generally 14–18 amino acids in length, for recogni- haploidentical SCT in humans. NK cells belong to the family of
+
tion by CD4 T cells. innate lymphoid cells. Unlike T and B cells, they do not express
+
The biologic mechanisms underlying the high incidence of graft rearranging receptors for antigen, but like CD8 T cells, they
rejection and severe GVHD when crossing the HLA barrier remain express receptors for HLA class I molecules, including HLA-B and
+
to be elucidated, but two fundamental characteristics of T-cell allo- HLA-C. Moreover, like CD8 T cells, they secrete interferon-γ and
reactivity are likely responsible. The first is the high frequency of T kill target cells via granzyme- and perforin-mediated cytotoxicity.