Page 1946 - Hematology_ Basic Principles and Practice ( PDFDrive )

1726 Part XI Transfusion Medicine

unknown conditions, HLA-F may modulate the function of immune forms HLA-Bw4. Because a single KIR can interact with multiple
effector cells similarly to HLA-E and HLA-G. HLA class I alleles, KIR recognition of HLA class I molecules is
degenerate. Another NK inhibitory receptor (CD94-NKG2A) recog-
NON-HUMAN LEUKOCYTE ANTIGEN POLYMORPHISM nizes the nonclassic HLA-E molecule. In addition, each of the KIR
genes is extensively polymorphic.
AND ITS CLINICAL SIGNIFICANCE Because the genes for KIR, HLA, and CD94-NKG2A are located
in separate chromosomes, they segregate independently and conse-
Although this chapter is dedicated to HLA, it would be incomplete quently individuals can carry genes for KIR for which there is no
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without mentioning the increasingly recognized polymorphisms of correspondent HLA ligand. As HLA-E is expressed in all individu-
other immune modulators. The significance of non-HLA polymor- als, NK cells that bear the CD94-NKG2A receptor are not alloreac-
phism is evidenced by the development of GVHD in the presence of tive. Because the specificity of KIR for their ligands is broad and each
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HLA identical matching among relatives. As recently summarized, individual carries several KIRs, it is likely that in most cases all NK
three general areas of polymorphism are being investigated: NK cell- cells of a given person express at least one KIR that is specific for a
receptor genes, mHags, and cytokines. Over the last decade, much self-HLA class I allele. Thus in autologous settings, NK cells kill only
progress has been made in identifying the mechanisms of action of aberrant cells that have lost HLA class I expression. By contrast, NK
NK cells. A major breakthrough was made in the discovery of HLA cells can kill allogeneic cells that do not express HLA class I alleles
class I-specific inhibitory receptors and in the role they play in the recognized by their KIR. Thus, by knowing the KIR repertoire of a
regulation of NK function with consequent effects on the eradication given transplant recipient and the HLA type of the donor, it would
of hematologic malignancies, prevention of graft rejection, or induc- theoretically be possible to predict the likelihood of an NK-mediated
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tion of GVHD. NK cells recognize HLA molecules via killer alloreaction. Importantly, it appears that alloreactive NK cells undergo
immunoglobulin-like receptors (KIRs). The regulation of NK cell proliferation on exposure to the stimulatory cells and therefore can
function by KIRs is further discussed in Chapter 22. KIRs are glyco- preferentially expand in the presence of allogeneic tissue. NK cells
proteins encoded by at least 17 different genes located on chromo- also express activating receptors that are responsible for their lytic
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some 19q13.4. All human KIR genes derive from a gene encoding activity. Although the identity of the ligands for these receptors has
three immunoglobulin (Ig)-like domains (D0, D1, and D2) and a not been identified, it is possible that they are expressed primarily by
long cytoplasmic tail. However, the KIRs genes are diverse and may activated or proliferating cells. It is therefore possible that during the
encode either two or three Ig-like domains and either a long or short inflammatory process induced in allogeneic conditions, normal cells
cytoplasmic tail (Table 113.1). The long cytoplasmic tails contain one can become activated by cytokines and express ligands, which are
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or two immunoreceptor tyrosine-based inhibition motifs. Although responsible for NK activation in the absence of HLA class I molecules
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KIR molecules with long cytoplasmic tails inhibit NK cytotoxicity, reactive with the inhibitory receptors. The relevance of KIR in
those with short tails do not. The names given to KIR genes are based transplantation has been well studied in the context of haploidentical
on the molecule that they encode. The first digit corresponds to the hematopoietic transplantation. In this case, several combinations are
number of Ig-like domains in the molecule and a D denotes domain. possible: NK cells from the graft express KIRs that do not interact
The D is followed by either an L for long cytoplasmic tail or S for with the donor’s HLA (graft-versus-host alloreactivity). It seems that
short cytoplasmic tail or p for a pseudogene. The last digit indicates the presence of graft-versus-host reactive NK cells associated with
the number of the KIR gene. 96 incompatibilities between donor and recipient (especially HLA-C
Expression of KIR in individual NK cells is complex because NK families) has favorable effects on the outcome of acute myeloid leu-
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cells may express several members of the KIR family. The number of kemia. Alternatively, a good match may be present between graft
KIR genes in each haplotype varies among individuals. The most NK and host HLA as well as between host NK and graft HLA. In
common haplotype is known as group A, and is made up of six genes such a case, no alloreactivity occurs. Finally, the graft’s HLA type may
(2DL1, 2DL2 or 2DL3, 3DL1, 3DL2, 2DS4, and 2DL4). Various be unsuitable for the host’s NK repertoire, and the host’s reactivity
KIR genes can recognize different HLA-A, HLA-B, and HLA-C may lead to graft rejection. Alloreactive grafted NK cells seem to
molecules. HLA-C antigens can be divided into two groups based on prevent GVHD while inducing GVN. 93
polymorphisms at amino acid positions 77 and 80 of their class I Like HLA, KIR genes are polymorphic, and their variability is
heavy chains. One group has asparagine (Asn) at position 77 and clustered in positions likely to affect the overall structure of the
lysine (Lys) at 80 and the other has serine (Ser) at 77 and Asn at 80. molecule. The relevance of KIR gene polymorphism in the outcome
Some KIRs recognize HLA-C antigens with Asn 77 and Lys 80, of hematopoietic stem cell transplantation (HSCT) is unclear. It
whereas other KIRs recognize HLA-C antigens with Ser 77 and Lys appears that the risk for GVHD is highest in the context of unrelated
80. The polymorphism at position 80 is most important. Another HSCT when the recipient KIR genotype is included in the donor
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group of KIR reacts with HLA-B antigens that carry specific combi- KIR genotype. These results show that compatibility between KIR
nations of amino acids at positions 77 and 83 of the heavy chain that genotypes themselves may influence the outcome of HSCT.
The mHags are represented by polymorphic molecules whose
peptides containing variant sequences are presented by HLA alleles.
They have been shown to be targets of cytotoxic T cells, which can
TABLE HLA Class I Alleles Recognized by Different Killer lyse leukemia cells. 98,100 In addition, some mHags are selectively
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113.1 Immunoglobulin-Like Receptors expressed by neoplastic cells. At present, little is known about the
identity of mHag epitopes in the context of various HLA types and
KIR HLA Class I Allele Amino Acid Sequence Motif their significance in the development of GVHD and GVN.
P58.1 (KIR2DL1) HLA-C2, HLA-C4, Asn 77, Lys 80 Cytokines are another large family of molecules associated with
HLA-C5, HLA-C6 antigen recognition, graft rejection, and GVHD. Their polymor-
phism is becoming an important area of investigation in the context
P58.2 (KIR2DL2/3) HLA-C1, HLA-C3, Ser 77, Asn 80 of transplantation, autoimmunity, and cancer. Polymorphic sites
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HLA-C7, HLA-C8
reside in regulatory regions so that genetic variants are associated with
P70 (KIR3DL1) HLA-Bw4 public Aa 77-83 high or low production of a given cytokine rather than differences in
specificity its function. A Web site compiles information about cytokine poly-
P140 (KIR3DL2) HLA-A3, HLA-A11 morphism (www.bris.ac.uk/Depts/PathAndMicro/services/GAI/
(KIR2DL4) HLA-G cytokine4.htm). Although no consensus has been achieved yet,
several studies have shown associations between various cytokine
Aa, Amino acid; Asn, asparagine; HLA, human leukocyte antigen; KIR, killer genotypes and propensity toward disease and transplant outcome.
immunoglobulin-like receptor; Lys, lysine; Ser, serine. 92,103
These studies have been summarized elsewhere. A strong