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2356 Part XIII: Transfusion Medicine Chapter 137: Human Leukocyte and Platelet Antigens 2357

massively parallel allowing for many overlapping reads of the same The graft may recognize the host tissue as foreign and mount an
sequence area. Multiple platforms using different chemistries are avail- immune response resulting graft-versus-host disease (GVHD). With
able; bioinformatics expertise is required to analyze the extensive data HLA-identical sibling donors, disease-free survival of greater than
provided by these methods. 80 percent can be achieved for some hematopoietic malignancies. 26,27
However, fewer than 30 percent of individuals have an HLA-identical
Detection of Antibodies to Human Leukocyte Antigen sibling. For these patients, alternative donors, such as phenotypically
Molecules matched unrelated volunteers and partially matched family mem-
In addition to typing for HLA antigens, most laboratories also use tech- bers, may be considered. However, the risks and incidence of graft
nology to detect antibodies to HLA antigens. This is very important for failure and GVHD are higher than seen with HLA-identical siblings,
solid-organ transplantation where the presence of anti-HLA antibodies and increase with the level of HLA disparity. HLA typing for stem cell
can cause irreversible rejection upon transplantation. It is of less con- transplants is generally performed by molecular methods. For those
cern for marrow/stem cell transplantation where donors and recipi- with a family donor, low-resolution typing may be sufficient to identify
ents are generally matched for HLA antigens. The microcytotoxicity a match. However for unrelated or haploidentical family donors, high-
serologic test is still in use, but solid phase assays have become stan- resolution (allele-level) typing for HLA-A, HLA-B, HLA-C, HLA-DR,
dard practice as they are more sensitive than the CDC method. These and HLA-DQ should be performed, and is required by the national
26
assays include enzyme-linked immunosorbent assay (ELISA) and registry program (National Marrow Donor Program [NMDP]). HLA
microbead-based flow assays such as FlowPRA and Luminex assays. alloantibody is becoming common, especially when incompletely
These tests require HLA antigen, in either recombinant or native form, matched donors are used.
bound to a solid surface such as a microsphere and used to capture Patients requiring platelet transfusions may be broadly sensitized
alloantibody in patient serum. Analysis of the reaction patterns yields to HLA-A, and -B (i.e., have high PRA) through prior transfusions (par-
information about the breadth of alloimmunization, or PRA (panel ticularly nonleukoreduced) or pregnancies. HLA antibody screening to
reactive antibody), and the specificity of the reactions. Prior to most select nonreactive donors and/or HLA donor platelet matching may
solid-organ transplants, a donor-specific crossmatch is also performed enable these refractory patients to achieve improved platelet transfusion
to ensure that the recipient does not have anti-HLA antibodies against count increments.
donor HLA antigens. Crossmatches are performed by microlympho- HLA typing at one or a few antigens or alleles may also be per-
cytotoxicity (CDC), flow cytometry, and by solid-phase (ELISA and formed to support diagnosis of diseases associated with specific HLA
microbead) assays. Labs are now adopting the “virtual” crossmatch antigens. The most common of these is the association between HLA-
28
using data from the sensitive microbead assays to predict crossmatch B27 and ankylosing spondylitis and HLA-DQ2’s association with nar-
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outcome. For low-risk cases this allows a transplant to proceed without colepsy. HLA typing may also be performed to determine eligibility
waiting for a physical crossmatch and shortens cold ischemic time for for vaccine trials that use peptides and HLA. 30,31 HLA antigens also are
*
an organ. 24 implicated in drug hypersensitivity. For example, HLA-B 5701 is asso-
ciated with hypersensitivity to the drug for treatment of the human
immunodeficiency virus, abacavir. 32
CLINICAL APPLICATIONS HLA tetramers may be used to monitor the efficacy of HLA-based
The HLA antigens coded by the MHC play a central role in transplan- peptide vaccines. Recombinant HLA molecules are loaded with the
tation, regulation of immune responses, and susceptibility to a vari- peptide vaccine and linked via a fluoresceinated streptavidin molecule.
ety of diseases. The most common application, however, is the field of They are incubated with patient blood lymphocytes. Effector T cells spe-
transplantation. In renal and stem cell transplantation, allografts from cific for the peptide-HLA will be bound by the tetramer and monitored
HLA-identical sibling donors have significantly greater survival than by flow cytometry.
grafts from nonmatched family or unrelated donors.
For solid-organ transplantation, a living donor is not always avail-
able or feasible (e.g., for heart transplantation). HLA typing for match-
ing of kidneys and pancreas is performed at the HLA-A, HLA-B, and NEUTROPHIL ANTIGENS
HLA-DR loci at low resolution (serologic or antigen level by DNA). AND ANTIBODIES
In the early years of renal transplantation a high degree of match was
sought between recipients and donors. However, as more potent immu- Clinically significant alloantigens expressed only or predominantly by
33
notherapies have developed, the level and use of HLA matching has neutrophils are known as human neutrophil antigens (HNAs). In this
declined. HLA matching is not prospectively performed for hepatic or nomenclature, the antigen systems are indicated by integers, and spe-
cardiac transplantation. Detection of alloantibody by screening tech- cific antigens within each system are designated alphabetically by date
niques and the donor specific crossmatch is of prime importance for of publication (Table 137–2).
kidney and heart transplants where its existence could cause a hyper-
acute rejection and graft failure. The role of alloantibody is less clear
in the immediate posttransplantation period, but may be detrimental THE HNA-1 ANTIGEN SYSTEM
to long-term survival. In the last several years, several “paired donor HNA-1 Antigens
25
exchanges” have arisen to assist recipients who have incompatible, but The neutrophil-specific HNA-1 antigen system is made up of the four
willing living donors. These programs, such as the National Kidney Reg- antigens alleles, HNA-1a, -1b, -1c and -1d (see Table 137–2). HNA-1
34
istry allow donor-recipient pairs to swap within or between transplanta- antigens are located on the low-affinity Fcγ receptor IIIb (FcγRIIIb),
tion centers. Chains of up to 30 cross-country swaps in the United States CD16, and are expressed only on neutrophils. 35–38 FcγRIIIb and HNA-1
have facilitated more than 1200 transplantations since its inception. antigens are expressed on all segmented neutrophils, on approximately
Marrow or stem cell transplantation entails problems other one-half of neutrophilic metamyelocytes, and on approximately 10 per-
than allograft survival. In these therapies an immunocompetent graft cent of neutrophilic myelocytes. Soluble FcγRIIIb is present in plasma
39
is transplanted to an immunocompromised/immunoablated host. and has the same HNA-1 polymorphisms found on neutrophils. 40

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