KIR matching in hematopoietic stem cell transplantation

KIR matching in hematopoietic stem cell transplantation Jean-Denis Bignon and Katia Gagne Although the key role of MHC-restricted T lymphocytes in hematopoietic stem cell transplantation (HSCT) has been known for a long time, recent data have focused on complementary or alternative effector cell populations, and in particular on NK cells. Spontaneously generated NK cell alloreactivity from stem cell grafts involves specific interactions between NK receptors, including killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands. The combined effects of HLA and KIR polymorphic genes might explain discrepancies in the impact of donor–recipient matching observed in HSCT. Addresses HLA laboratory, Etablissement Franc¸ais du Sang, Pays de Loire, 34 Boulevard Jean Monnet, 44011 Nantes, France Corresponding author: Bignon, Jean-Denis ([email protected])

Current Opinion in Immunology 2005, 17:553–559 This review comes from a themed issue on Transplantation Edited by Frans Claas Available online 8th August 2005 0952-7915/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2005.07.014

Introduction Hematopoietic stem cell transplantation (HSCT) is currently used in the treatment of a variety of hematological malignancies including chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). The efficacy of HSCT, however, remains limited by several significant complications such as failure of the hematopoietic stem cells (HSC) to engraft, the occurrence of graft-versus-host disease (GvHD), relapse and the susceptibility of patients to opportunistic infections during the post-transplantation immunodeficiency period. Although the key role of MHC-restricted T lymphocytes has been known for a long time, recent data have focused on complementary or alternative effector cell populations, particularly on NK cells. In fact, T lymphocytes and NK cells can be both beneficial and deleterious in HSCT. Donor T cells within the allograft are vital in promoting engraftment, eradicating malignant cells (graft-versus-leukemia [GvL] effect) and reconstituting www.sciencedirect.com

immunity. NK cells also mediate GvHD, however, resulting in the destruction of recipient tissues. Recipients are also at high risk from their own T cell-mediated responses in the host-versus-graft (HvG) disease. These T cellmediated responses are MHC restricted and involve incompatibilities of both major HLA class I and class II antigens and/or multiple minor histocompatibility disparities. T cell-mediated responses can largely be controlled by appropriately adjusting the immunosuppressive intensity of the conditioning regimen so as to prevent graft rejection and/or by extensive graft T cell depletion to prevent GvHD. Unfortunately, T cell depletion is not only associated with an increased incidence of disease relapse but also with HSCT failure. NK cells appear rapidly following HSCT and are prevalent for three months (representing up to 70% of peripheral blood lymphocytes [PBLs]) [1,2]. These NK cells could exert beneficial alloreactive effects, as clearly observed in T cell depleted HSCT [3]. Recent data concerning alternative effector cell populations have focused precisely on NK cells, which are pivotal effectors in the non-MHC-restricted cytotoxic cell family. NK cells play an important role as cytotoxic effectors and as a source of cytokines, and might also contribute to antileukemia effects. Recently, Ruggeri et al. [3] reported clinical data showing that spontaneously generated NK cell alloreactivity from stem cell grafts was associated with a remarkable GvL effect and a total control of rejection and acute GvHD. This review analyses the last ten studies published between 2002 and 2005 concerning the effects of KIR and KIR ligand mismatching on NK alloreactivity in HSCT.

NK cells and KIR receptors The NK subset, which represents about 10 percent of PBLs, is characterized by expression of CD56 and CD16 and absence of CD3 and CD4 [4]. The main functions of NK cells are regulated by the expression of NK receptors (NKRs) including a family of polymorphic Ig-like molecules known as killer cell immunoglobulin-like receptors (KIRs) that either block or enhance their cytotoxicity (reviewed in [5]). KIRs do not have the antigen recognition specificity of T cell receptor lymphocytes, but are able to recognize groups of HLA class I molecules including HLA-A (A3, A11), HLA-B (Bw4) and HLA-CwLys80 or -CwAsn80 antigen subgroups (Table 1). Despite the multiplicity of KIR–HLA class I ligand interactions [6–8], the most dominant patterns of alloreactivity are those arising due to an asparagine/lysine dimorphism located at Current Opinion in Immunology 2005, 17:553–559

554 Transplantation

Table 1 Killer cell immunoglobulin-like receptors. Receptor

Ligand

2DL1 2DL2,3 2DL4 2DL5 3DL1 3DL2 3DL3 2DS1 2DS2 2DS3 2DS4 2DS5 3DS1

1

Function Lys80

HLA-Cw HLA-Cw Asn80 HLA-G Unknown 3 HLA-Bw4 HLA-A3, A11 ? EBV peptide Unknown 1 HLA-Cw Lys80 2 HLA-CwAsn80 ? Unknown HLA-CwLys80 ? Unknown Unknown 2

Inhibitory Inhibitory Inhibitory/activating Inhibitory/activating Inhibitory Inhibitory Inhibitory Activating Activating Activating Activating Activating Activating

1

HLA-CwLys80: Cw*02, *0307/10/15, *04, *05, *06, *0707/09, *1204/05, *15 (except *1507), *1602, *17, *18. 2HLA-CwAsn80: Cw*01, *03 (except *0307/10/15), *07 (except *0707/09), *08, *12 (except *1204/05), *13, *14, *1507, *16 (except *1602). 3 HLA-Bw4: a chain amino acids 80–83 (Ile-Ala-Leu-Arg).

position 80 of the HLA-Cw heavy chain [9]. Cells from an asparagine 80 homozygote recipient will be killed by donor NK cell clones expressing KIR2DL1, whereas cells from a lysine 80 homozygote recipient will be killed by donor NK cell clones expressing KIR2DL2 and/or KIR2DL3 [10]. The normal process of NK cell development ensures that circulating NK cells tolerate healthy autologous cells due to the interaction of inhibitory NK cell receptors with autologous HLA class I ligands [11]. Conversely, NK cell alloreactions are directed towards allogeneic cells that lack self-MHC class I molecules. In HLA class I mismatched HSCT, it is already known that alloreactive NK cells derived from the graft are able to kill leukemia cells and prevent the leukemia relapse [3,10]. Because KIR and HLA genes are located on different chromosomes (19 and 6, respectively), they are inherited separately, and KIR mismatching can be observed in HLA matched sibling pairs. The combined effects of these two HLA and KIR polymorphic sets of independent genes can therefore explain discrepancies in the HLA matching effect observed in HSCT [12,13].

HLA matching in hematopoietic stem cell transplantation Whereas the best outcome is observed following HSCT between HLA-identical siblings, the alternative of using transplants from unrelated donors is increasing due to the availability of more than 9.5 million donors worldwide. When a perfectly HLA-matched donor is not available, selection is based on the best HLA matching considering class I (HLA-A, -B, -Cw) and class II (-DRB1, -DQB1) loci. Controversies remain as to whether mismatches at some HLA loci have more deleterious clinical effects. Many conflicting data have been reported over the past 10 years [12–19]. Thus, HLA class I matching was critical in a Japanese cohort [12] whereas HLA-DRB1 was the most Current Opinion in Immunology 2005, 17:553–559

important factor in a Caucasian cohort [17]. These discrepancies could be partly explained by numerous factors, including the size and ethnicity of patient cohorts, the choice of related or unrelated donors, the diagnosis and stage of disease, the conditioning regimen, potential T cell depletion and the nature of the stem cells infused. Moreover, the accuracy and resolution levels of HLA typings have evolved during this period. In a recent article, Flomenberg et al. [20] reported the real impact of high resolution HLA class I and II matching in 1874 donor–recipient pairs. In contrast to mismatches for HLA-DQB1 or -DPB1, high-resolution mismatches at HLA-A, -B, -Cw and -DRB1 adversely affected outcome. In particular, HLA-Cw mismatching was associated with a strong adverse effect on transplantation outcome, suggesting that HLA-C exerts significant effects on survival comparable in magnitude to HLA-A, -B and -DRB1. In the same issue of Blood, Van Rood emphasized that ‘HLA-C alleles can no longer be ignored in bone marrow donor selection’ [21]. Given these findings, the first data presented by Ruggeri in 2002 [3] could be considered as strange, because unusual HLA-C mismatching was associated with a significantly increased overall survival (OS), a better engraftment and a reduced incidence of GvHD [3]. Thus, despite this HLA mismatching, transplantation using an HLA-non identical donor provides an unique setting in which donor NK cells can contribute to anti-leukemia effects [22]. These controversies concerning the effects of HLA mismatching could be explained by the potential NK alloreactivity linked to both KIR and KIR-ligand mismatching between donor and recipient.

KIR and KIR-ligand mismatching in hematopoietic stem cell transplantation HLA mismatching can, in some instances, be a KIRligand mismatching, described by Klas Ka¨ rre as a perfect mismatch [22], potentially leading to beneficial NK alloreactivity. Such an effect was statistically significant in related, T cell depleted and HLA-mismatched HSCT, as reported initially by Ruggeri et al. [3]. The impact of KIRligand mismatching, however, has been associated with controversy, particularly in unrelated HSCT. For this reason, we attempted to compare the last ten publications dating from 2002 [3] to 2005 [23,24] concerning the effects of KIR and/or KIR-ligand mismatching on HSCT. These controversies need to be clearly analyzed and such an analysis should take into account the statistical tests performed as well as the clinical study endpoints. Indeed, OS, disease-free survival (DFS) and transplant-related mortality (TRM) are predominantly determined by the pre-transplant disease stage and patient age [23]. For the purpose of determining the impact of KIR and KIRligand mismatching, however, relapse, acute GvHD, and to some extent primary graft failure and consequently OS will be considered in this review. www.sciencedirect.com

KIR matching in HSCT Bignon and Gagne 555

Depending on the study, significant beneficial or deleterious effects of NK alloreactivity have been observed for each of the above parameters (OS, primary graft failure, relapse and acute GvHD; Table 2). A positive outcome, including OS, decreasing acute GvHD, graft failure and relapse, has been demonstrated in the setting of haploidentical HSCT [3]. In the same year, we showed an interesting effect of donor–recipient KIR gene mismatching on acute GvHD risk, mainly in unrelated HSCT [25]. In a study involving heterogeneous unrelated donor transplant recipients, no beneficial effect on aGvHD, graft failure or relapse were observed and the authors concluded that KIR ligand incompatibility conferred no advantage [26]. Conversely, in a similar study of 130 unrelated HSCT pairs, where all patients received anti-thymocyte globulin (ATG), recipients with a KIR ligand incompatibility had higher probability of OS (p = 0.006) and DFS (p = 0.0007) compared with those without KIR ligand incompatibility [27]. Bornha¨ user et al. [28] and Bishara et al. [29] also failed to confirm any beneficial effects related to KIR ligand mismatching. In the same year, two other studies even reported deleterious effects of KIR ligand mismatching, which could be related to the effect of the donor KIR2DS2 activating gene in HLA identical sibling HSCT [30] or to an increased infection-related mortality [31] in unrelated HSCT. Nevertheless, more recently in a very well documented study, Hsu et al. [24] reported an improved outcome in AML/myelodysplastic syndrome (MDS) patients receiving a T cell depleted HSCT from an HLA-identical sibling donor when both KIR and HLA genotypes were considered. Furthermore, when analyzing unmodified allogeneic HSCT, Beelen et al. [23] showed that primary graft failure rates increased significantly when using KIR ligand incompatible donors compared to HLA class I identical or HLA class I disparate donors; however, they also showed that the use of KIR ligand incompatible donors results in a superior long term

anti-leukemic effect in patients with myeloid malignancy illustrated by the low rate of relapse in this subgroup. Overall, these discrepancies in the literature could be due to numerous parameters possibly reflecting different levels of heterogeneity linked to either patient and graft or HLA and KIR gene matching.

Patient and graft parameters First of all, among the ten studies reported (Table 3), four groups analyzed only related HSCT [3,24,29,30], four analyzed unrelated HSCT [26–28,31] and two groups analyzed a pool of both HSCT pairs [23,25]. The related pairs were either HLA identical or haploidentical, and included the initial report by Ruggeri [3]. Moreover, and probably most importantly, only four out of ten reports clearly mentioned an unique source of the HSC used (Table 3) as well as the purity and quantity of CD34+ grafted cells [26]. In particular, the proportion of contaminating donor T cells inoculated depends on the medullar or peripheral origin of the HSC, as noted by Parham and McQueen [10]. Although peripheral blood stem cells contain ten times more T cells than medullar grafts, the two sources produce comparable levels of GvHD [32,33]. The degree of T cell depletion could also interfere with the numbers of residual T cells [24]. Consequently, the beneficial role of NK alloreactivity is less clear in the presence of GvHD caused by these residual alloreactive T cells, as reported by Bishara et al. [29], and as proven in murine models of GvHD [34,35]. In this context, the use of ATG during conditioning and as GvHD prophylaxis has been emphasized [36]. Nevertheless, differences in age, stem cell source, increased graft failure and disease stage, could influence the effect of ATG-mediated T cell depletion, explaining discrepancies between two studies where ATG was used [27,28]. Moreover, during the first three months posttransplantation, cytomegalovirus (CMV) infection or

Table 2 Significant beneficial and deleterious effects of KIR marker and/or KIR ligand mismatches in HSCT. Authors [reference]

Overall Survival (OS)

aGvHD

Primary graft failure

Relapse

Ruggeri et al., 2002 [3] Gagne et al., 2002 [25] Davies et al., 2002 [26] Giebel et al., 2003 [27] Bornha¨ user et al., 2004 [28] Bishara et al., 2004 [29] Cook et al., 2004 [30] Schaffer et al., 2004 [31] Beelen et al., 2005 [23] Hsu et al., 2005 [24]

B nt D B NS D D3 D4 N.S B6

B D1 NS NS NS D2 NS NS NS NS

B nt NS NS nt NS nt NS D nt

B nt NS NS D NS NS NS B5 B6

Only donor and recipient KIR genotyping were analyzed. 2NK alloreactivity in the GvHD direction was associated with an increased prevalence of aGvHD (III-IV) and poorer patient survival. A higher number of activating KIR genes in the donor was also associated with a higher prevalence of aGvHD. 3Deleterious effect only observed for myeloid disease patients when donor carried the activating KIR2DS2 gene. 4 A higher rate of infections was responsible for this deleterious OS effect. 5Only myeloid leukemia patients were analyzed. 6Beneficial effects were limited mainly to AML/MDS patients. B, beneficial; D, deleterious; NS, no significant effect; nt, not tested. 1

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556 Transplantation

Table 3 Patient and graft parameters of KIR and/or KIR ligand matching studies in HSCT. Authors [reference]

Number of D/R pairs

Source of HSC

% of T-cell depleted grafts

HSCT type

D/R HLA matching

Diagnosis

Combined KIR and KIR-ligand studies

Ruggeri et al., 2002 [3]

92

Unknown

100%

RD

Haploidentical

AML (62%), ALL (38%)

No

Gagne et al., 2002 [25]

75

BM

9%

RD (45%) and UD (55%)

HLA-m (75%) HLA-mm (25%)

ALL (28%), AML (21%), CML (24%), others (27%)

No

Davies et al., 2002 [26]

175

BM

34%

UD

HLA-mm

ALL (20%), AML (8%), CML (33%), MDS (5%)

No

Giebel et al., 2003 [27]

130

BM (96%)

Unknown

UD

HLA-m (47%) HLA-mm (53%)

ALL (29%), AML (17%), CML (32%), MDS (18%)

No

Bornhau¨ ser et al., 2004 [28]

118

Mixed

Unknown

UD

HLA-m (46%) HLA-mm (54%)

AML (50%), CML (38%), MDS (12%)

No

Bishara et al., 2004 [29]

62

PBSC

No extensive T-cell depletion

RD

Haploidentical

ALL (39%), AML (24%), CML (21%), others (16%)

Yes/no 1

Cook et al., 2004 [30]

220

Unknown

Unknown

RD

HLA-m

ALL, CLL, NHL (49%); AML, CML, MDS (51%)

Yes

Schaffer et al., 2004 [31]

190

Mixed

Unknown

UD

HLA-m (49%) HLA-mm (51%)

ALL (23%), AML (31%), CML (37%), MDS (9%)

No

Beelen et al., 2005 [23]

374

Mixed

0%

UD (60%) and RD (40%)

HLA-m (63%) HLA-mm (37%)

AML/MDS (37%), CML (63%)

No

Hsu et al., 2005 [24]

178

BM

100%

RD

HLA-m

ALL (25%), AML (32%), CML (34%), MDS (9%)

Yes

1

KIR and KIR ligand matching were analyzed separately. ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; BM, bone marrow; CML, chronic myeloid leukemia; D, donor; HLA-m, HLA-matched pairs; HLA-mm, HLA-mismatched pairs; HSC, hematopoietic stem cell; MDS, myelodysplastic syndrome; mixed, BM plus PBSC; NHL, non-Hodgkin lymphoma; PBSC, peripheral blood stem cells; R, recipient; RD, related donor; UD, unrelated donor.

reactivation can modulate the NK repertoire and subsequently NK alloreactivity [36]. The conflicting data reported in Table 2 could, at least in part, be due to heterogeneities in numbers and hematological diseases of the patients included; thus, NK alloreactivity might only be beneficial in AML patients, as initially reported by Ruggeri [3].

HLA and KIR gene matching The majority of studies published so far have focused only on KIR ligand mismatches concerning the three major HLA class I specificity groups recognized by inhibitory KIRs (Table 1). These will only become potenCurrent Opinion in Immunology 2005, 17:553–559

tially beneficial mismatches or ‘perfect mismatches’ if a donor NK genotype displays the corresponding inhibitory KIRs (i.e. KIR2DL1, KIR2DL2/2DL3 and/or KIR3DL1) and if the corresponding HLA ligand (KIR ligand mismatch) is absent in the recipient. This is the main mechanism leading to a GvL effect by reducing relapse rate, a decrease in aGvHD risk by destroying recipient antigen presenting cells (APCs) and consequently to an improvement in OS [3]. In order for this beneficial NK alloreactivity process to be observed, HLA and KIR genotyping is necessary, even in related HSCT, because KIR and HLA haplotypes segregate independently. All KIR population studies so far show that very few www.sciencedirect.com

KIR matching in HSCT Bignon and Gagne 557

individuals lack KIR3DL1 and KIR2DL1 genes [7,8,11,25,37,38]. Thus, as claimed by Dupont and Hsu [39], most individuals have inhibitory KIR for all HLACw molecules, but the opposite is not necessarily true. The same authors clearly stated that KIR-driven alloreactivity in the transplant setting might be better predicted if the donor KIR genotype is considered in addition to the HLA genotype of the recipient [24]. The expressed KIR repertoire of an individual, however, is primarily dependant of KIR genotype but not HLA genotype [40–44,45]. This was confirmed by phenotyping peripheral NK cells, which indicated that the HLA genotype has little impact on the KIR repertoire [46]. NK repertoire expression remains difficult to establish because of the unavailability of specific monoclonal antibodies. Moreover, the expression of some relevant donor KIR genes might be downregulated during hematological reconstitution following HSCT, particularly when myeloablative conditioning is used. We recently studied transcriptional KIR repertoires in grafted patients using real-time reverse-transcription polymerase-chain-reaction. Three groups of patients were identified and twothirds were characterized by the absence or a delayed appearance of KIR transcripts. In the remaining third, a significant, but specifically limited, transcript peak was observed early on. These KIR transcript kinetics correlate with aGvHD risk [47]. Moreover, KIR genes are known to be polymorphic [48,49], and this increasing allelic polymorphism might affect KIR receptor expression and ligand affinity [43,50]. Thus, only a combined HLA and KIR genetic study considering relevant HLA class I mismatches leading to the absence of a KIR-ligand in the recipient and the presence of corresponding donor KIR will enable a better evaluation of the real impact of NK alloreactivity in HSCT [45].

genetic rules determining NK alloreactivity should help to select donors through additional but limited donor KIR genotyping. Nevertheless, studies should also consider the functional allelic polymorphism of inhibitory KIR genes. The impact of activating KIR genes should also be analyzed, even if the corresponding ligands have not yet been identified for the majority. Variability in the transcriptional KIR repertoire, at least during the early period of engraftment, and consequently at the expression level, could also explain the difficulty in understanding NK alloreactivity. Studies of NK alloreactivity may also be modulated by viral reactivations or infections in HSCT recipients exposed to an immunosuppressive therapy. Results from the first studies show the importance of selecting donor–recipient pairs limiting graft parameter diversity in order to properly establish the genetic rules of NK alloreactivity. A better understanding of how NK alloreactivity can be exploited in HSCT has to take into account not only KIR and KIR-ligand mismatching but also phenotype and function of alloreactive NK cells. Taken together, all of these studies will provide fundamental insights into allogeneic NK cell effects, which could determine the usefulness of NK cell based immunotherapy in recipients of mismatched HSCT [51,52].

Acknowledgements The authors thank Anne Cesbron-Gautier, Anne Devys, Christelle Retie`re, Laure Denis (Etablissement Franc¸ais du Sang, Nantes, France) for critically reviewing the manuscript and Joanna Ashton-Chess (Inserm U643, Nantes, France) for editing the manuscript. This work was supported by grants from Etablissement Franc¸ais des Greffes, La Ligue contre le Cancer and Etablissement Franc¸ais du Sang.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest

Conclusions Until now, HSCT with a fully HLA matched donor was significantly associated with the best OS because, in the majority of cases, the deleterious effect of T cell alloreactivity is limited. Nevertheless, the unavailability of HLA identical donors (related sibling or unrelated), which means choosing a partially HLA matched donor, should no longer be considered as deleterious. Since 2002, many studies in the literature have tried to understand the complicated NK cell alloreactivity, which could mediate beneficial effects in HSCT. The NK cell alloreactivity mechanism is not yet fully understood, but could be primarily related to a decrease in relapse due to a GvL effect and aGvHD risk. As NK cells are the first cells to appear, NK alloreactivity probably arises in the early postHSCT period and is rapidly masked by T cell alloreactivity. Although HLA matching still remains the first step to selecting the best donor, a better understanding of the www.sciencedirect.com

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Current Opinion in Immunology 2005, 17:553–559