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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-04-1197.
BRIEF REPORT
From the Blood and Marrow Transplant Program,
University of Minnesota, Minneapolis; and Department of Clinical and
Experimental Medicine, Division of Hematology and Clinical Immunology,
Perugia University School of Medicine, Perugia, Italy.
One of the functions of HLA class I alleles is interaction with
natural killer (NK) cells. Receptors termed killer immunoglobulinlike receptors (KIRs) on NK cells recognize groups of HLA class I alleles, and interaction between receptor and class I allele inhibits reactivity of the NK cell. Failure to recognize the appropriate KIR ligand on a
mismatched cell can trigger NK cell elimination of that target cell.
Recent analysis of haploidentical hematopoietic transplantations has
shown a reduction of graft failure, graft-versus-host disease, and
relapse in those with KIR ligand incompatibility in the
graft-versus-host direction. In this study we analyzed the
effect of KIR ligand incompatibility on outcomes of unrelated donor
bone marrow transplantations. The data show no advantage for
KIR ligand incompatibility in this clinical setting as assessed by
HLA-Bw4 and HLA-C alleles. It is possible that there will be a benefit
of NK cell alloreactivity if strategies of haploidentical
transplantation are used: high stem cell doses, extensive T-cell
depletion, and no postgrafting immune suppression.
(Blood. 2002;100:3825-3827) One of the important functions of HLA class I
alleles is interaction with natural killer (NK) cells. Receptors termed
killer immunoglobulinlike receptors (KIRs) on NK cells recognize groups of HLA class I alleles.1,2 Failure to recognize the
appropriate KIR ligand on a mismatched cell triggers NK cell
cytotoxicity. The consequences of NK cell alloreactivity, based on KIR
ligand matching as determined by HLA class I typing, have recently been explored in haploidentical transplantation.3 That study
analyzed NK function, using donor NK clones and recipient cells as
targets, and correlated this activity with HLA-typing. A highly
predictable algorithm for NK cell function was devised based on these
HLA-typing results, which was then used for analysis of clinical end
points. The previously published data demonstrated that
donor-versus-recipient NK cell alloreactivity could eliminate leukemia
relapse and graft rejection and protect patients against
graft-versus-host disease (GVHD). In this study we have applied the
same paradigm to recipients of unrelated donor transplants with
mismatch at class I loci to start to address the generalizability of
this algorithm in recipients of unrelated donor bone marrow transplants
(BMTs) in the United States, transplanted at a single institution.
Patients
No significant differences were identified between those with
and without KIR ligand incompatibility in recipient age, diagnosis, stage of disease, preparative regimen, or GVHD prophylaxis (Table 1).
There was no difference between the 2 groups in the year of the
transplantation procedure (data not shown).
Graft-versus-host disease
Statistical analysis Data regarding transplantation patient characteristics, posttransplantation complications, and outcomes were prospectively collected by the Biostatistical Support Group using standardized collection procedures. Cumulative incidence rates and 95% confidence intervals (CIs) were estimated for engraftment, grades II to IV and grades III to IV acute GVHD, and relapse (for patients with malignant diseases).5 Kaplan-Meier methods were used to estimate survival.6 Log-rank test statistics were used to evaluate the univariate effects of KIR ligand incompatibility on outcome. To evaluate the independent effect of KIR ligand incompatibility, Cox regression was performed.7 Factors included in the models were recipient and donor age, diagnosis, GVHD prophylaxis, conditioning regimen, and HLA mismatch.
KIR ligand status, according to the algorithm generated by Ruggeri
et al,3 was determined for each donor-recipient pair. Incompatibility was assigned if a donor KIR ligand class I allele was
not present in the recipient. Thus, donor NK clones are not inhibited
by a ligand expressed on recipient cells. The algorithm provided a high
degree of correlation between NK functional activity and HLA typing in
haploidentical donor-recipients pairs.3 The presence of
donor alloreactive NK cells should eliminate host antigen-presenting
cells and host tumor cells, thereby diminishing rejection, GVHD, and
residual tumor burdens. However, in our population of unrelated donor
patients, no significant differences were seen in survival or acute
GVHD grades III to IV (Table 2).
There was a trend toward an increased frequency of grades II to IV GVHD in those with KIR ligand incompatibility (61% versus 50%, P = .09). These data differ from the report of Ruggeri et al3 in which the presence of KIR ligand incompatibility was associated with protection from graft failure, GVHD, and relapse.3 Much of the benefit of KIR ligand incompatibility reported by Ruggeri et al3 was seen in those with acute myelogenous leukemia. We reanalyzed the data, including only those with myeloid disease (acute myelogeneous leukemia [AML], n = 14; chronic myelogeneous leukemia [CML] = 58). No substantial differences were found between those with and without KIR ligand incompatibility in recipient age, diagnosis, stage of disease, preparative regimen, or GVHD prophylaxis (data not shown). Analysis of outcomes showed no differences between those with and without KIR ligand incompatibility in the end points of graft failure, GVHD, or relapse (Table 2). Survival was better in those without KIR ligand incompatibility (38% [95% CI, 24-52] versus 13% [95% CI, 0-26] at 5 y, P < .01). This difference in survival was surprising, as an advantage for KIR ligand incompatibility was expected.3 The present data might reflect an increased number of HLA mismatches in the KIR ligand mismatched group. Analysis of the total number of class I mismatches shows a significantly higher number of class I allele level mismatches in myeloid cases with KIR ligand incompatibility (46% versus 12% with > 2 allele level mismatches, P < .01). However, this does not explain the survival difference seen, as inclusion of the number of HLA mismatches in a Cox regression model did not substantially change the effect of KIR ligand incompatibility on mortality. The relative risks of KIR ligand incompatibility on mortality with and without HLA mismatch included were 2.2 (95% CI, 1.3-4.0) and 2.7 (95% CI, 1.3-5.4), respectively. The full haplotype-mismatched transplantations reported by Ruggeri et al3 were performed by using a high CD34+ cell dose for engraftment, combined with extensive T-cell depletion to prevent GVHD, such that no postgrafting immunosuppression was needed. Such transplantations are typically associated with rapid recovery of NK cells and slow T-cell recovery.8-10 In contrast, two thirds of the unrelated donor transplantations we report were not T-cell depleted. In addition, the transplantations that were T-cell depleted were treated with elutriation that typically yields a 2-log T-cell depletion.11 This finding is much less than the 4-log depletion used in haploidentical transplantation. The different schedules of immune reconstitution might have masked any potential role for NK cell alloreactivity in influencing outcome. Because the donor grafts in our study contain a higher number of T cells than those of Ruggeri et al,3 the NK cell effects may have been obscured by donor T-cell effects and/or the immune suppression necessary to prevent/control GVHD caused by higher numbers of donor T cells. The report by Ruggeri et al3 focused on acute leukemia, and the important influence of KIR ligand incompatibility on relapse rates was seen in those patients with AML. In this study we examined CML and AML, but if the role of alloreactivity is clinically evident only in AML, we may have had too few AML cases to detect the NK effect. The current study suggests that the beneficial effects of KIR ligand incompatibility in the GVHD direction observed in haploidentical transplantations are not generalizable to unrelated donor BM transplantations. The study of haploidentical transplantations provided direct evidence that KIR ligand incompatibility in the GVH direction is, with no exception, predictive of donor-versus-recipient NK cell alloreactivity. In the present study no functional assessment of the donor's NK cell repertoire was performed. It is therefore possible that stimulatory receptors, KIRs yet to be identified, or NK cell receptors from other families (eg, NKG2a/CD94 heterodimers) may play a role in the outcome of unrelated donor transplantations or confound known KIR/KIR ligand interactions.12,13 However, analyses of 32 unrelated pairs of healthy individuals indicate KIR ligand mismatches are predictive of NK cell mismatches even among genetically unrelated individuals (A.V. and L.R., unpublished data, April, 2002). An AML-specific effect might be observed in unrelated donor transplantations only if strategies from haploidentical transplantations are used: (1) transplantation of high doses of stem cells, (2) extensive T-cell depletion, (3) no postgrafting immunosuppression, and (4) donors selected for the "perfect mismatch" at HLA loci to drive favorable NK cell-mediated effects. Prospective studies are needed to address these possibilities.
Submitted April 19, 2002; accepted June 20, 2002.
Prepublished online as Blood First Edition Paper, July 5, 2002; DOI 10.1182/blood- 2002-04-1197.
Supported by grants from the Italian Association for Cancer Research, the Italian Ministry of Research, the Italian Ministry of Health, and by a translational grant from the Leukemia and Lymphoma Society (A.V.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Stella M. Davies, University of Minnesota, 422 Mayo Mail Code, 420 Delaware St SE, Minneapolis, MN 55455; e-mail: davie008{at}umn.edu.
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Top
Abstract
Introduction