Journal of Clinical Immunology

, Volume 27, Issue 1, pp 109–116

The Effect of Natural Killer Cell Killer Ig-Like Receptor Alloreactivity on the Outcome of Bone Marrow Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID)

Authors

  • M. D. KELLER
    • Division of Pediatric Allergy and ImmunologyDuke University Medical Center
  • D.-F. CHEN
    • Clinical Transplantation Immunology LaboratoryDuke University Medical Center
  • S. A. CONDRON
    • Duke School of MedicineDuke University Medical Center
  • N. LIU
    • Clinical Transplantation Immunology LaboratoryDuke University Medical Center
  • N. L. REINSMOEN
    • Clinical Transplantation Immunology LaboratoryDuke University Medical Center
    • Division of Pediatric Allergy and ImmunologyDuke University Medical Center
    • Duke University Medical Center
Original Paper

DOI: 10.1007/s10875-006-9058-7

Cite this article as:
KELLER, M.D., CHEN, D., CONDRON, S.A. et al. J Clin Immunol (2007) 27: 109. doi:10.1007/s10875-006-9058-7

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient–donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (R2 = 0.95, p = 0.84), development of T-cell function (R2 = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (R2 = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.

KEY WORDS

Natural killer cellsImmunodeficiencyKiller Ig-like receptorsHematopoietic stem cell transplantation

INTRODUCTION

Severe combined immunodeficiency (SCID) is a fatal genetic disorder characterized by the presence of lymphopenia, absence of T cells, and extreme susceptibility to infection (1). Since its initial description, 12 distinct genes have been shown to result in SCID when mutated (1). The incidence of SCID has been estimated at between 1 in 30,000–70,000 live births (2), however no studies have been performed to establish the true rate. The current treatment of choice is hematopoietic bone marrow stem cell transplantation (HCT) which, if given during the first 3.5 months of life, has been shown to result in long-term survival of up to 96% of patients (3). Although HLA-identical related transplants are ideal, methods of rigorous T-cell depletion have made haploidentical parental marrow transplantation a successful alternative (1, 3, 4), with relatively low rates and severity of graft-versus-host disease (GVHD). Due to their lack of T cells, patients with SCID cannot mount an adaptive immune response to allografts, thus allowing HCT to be performed successfully without preconditioning by irradiation or chemotherapy.

Natural killer (NK) cells have been well-studied in the field of HCT (57). As a link between adaptive and innate immunity, NK cells are able to function as either cytokine producers or cytotoxic effectors. NK cells can mediate cytotoxicity by both antibody-dependent means (ADCC) or via NK receptor families, many of which interact with MHC class I ligands. NK receptor families include the C-type lectin-like family, natural cytotoxicity receptors (NCR), and Killer-Ig-like receptors (KIR), which make up the “NK synapse” (8). Both the KIR and C-type lectin-like families possess activating and inhibitory receptors, which are expressed variably on subsets of NK cells. These receptors are believed to trigger reactions in response to missing individual class I MHC ligands on target cells, which may occur as a result of viral infection or tumor (9). With regard to KIR inhibitory receptors, the interaction of KIR3DL1 with HLA-Bw4 has been well described (10), as has the interaction of KIR2D with HLA-C, with the specificity for KIR2DL1 versus KIR2DL2/3 dependent on the presence of either a Ser77Asn80 or Asn77Lys80 motif, respectively, in HLA-C (11).

SCID resulting from mutations in common γ chain, Janus kinase 3 (JAK3), or adenosine deaminase (ADA) is characterized by low to absent NK cells, presumably due to an inability to signal through the IL-15 receptor in the case of γc and JAK3 deficiencies (12) or to destruction by toxic metabolites in the case of ADA deficiency (13). Other forms of SCID generally have normal NK cell presence and function. Following HCT for SCID, it has been seen that NK cells are among the first lineages to appear following engraftment (14). These cells generally have normal cytotoxic function (unpublished observations), and previous studies in transplanted SCID infants showed these early NK cells to be of donor origin (15 and unpublished observations). Analyses of KIR reconstitution following HCT have given mixed results (1618), though several investigations have noted that the KIR expression pattern reapproximates the donor's KIR repertoire within 3 months of HCT when pretransplant conditioning is given. The absence of an MHC class I ligand in the recipient for donor KIR may allow the development of potentially alloreactive subsets of engrafted NK cells, the clinical impact of which was demonstrated by Ruggeri et al. in recipients of HCT for myeloid leukemia, for whom the absence of an inhibitory KIR ligand in recipients for donor KIR resulted in significantly decreased tumor relapse, decreased rates of GVHD, and increased survival rates (19). Mouse models have further shown the power of KIR alloreactivity in preventing GVHD and facilitating successful engraftment of marrow allografts, possibly by mediating the killing of host antigen presenting cells (20). Subsequent retrospective studies have confirmed the effect in myeloid leukemia, although effects in HCT for other conditions have been less clear (2124). No large studies have been performed examining KIR effects on bone marrow transplantation for human SCID.

Of further interest is the role of the murine Ly49 family in the “hybrid resistance” mouse model, in which lethally irradiated F1 hybrid mice will reject parental marrow allografts in an NK-dependent manner (2527). Clinical observations suggesting increased resistance to engraftment following HCT for SCID in patients possessing normal NK cells has led to the postulate that human NK cells may similarly mediate graft rejection (28). Despite their lack of homology, the similar functions of Ly49 and KIR have caused some to hypothesize that host-versus-graft alloreactions in this context could be mediated by KIR (29).

In this study, we explored whether absence of recipient KIR ligands for donor KIR resulted in beneficial graft-versus-host alloreactions that affected clinical outcomes in transplantation for SCID. We further studied whether KIR-mediated HVG reactions may be occurring in SCID patients who possess NK cells.

METHODS

Patients

A total of 156 patients with SCID received allogeneic bone marrow transplants at this institution from 5/13/82 through 9/11/06, of which only 137 could be studied due to genetic material limitations. Median age at transplantation was 165 days (range: 7–597 days). Molecular basis of SCID was γc deficiency in 64, IL-7Rα deficiency in 15, ADA deficiency in 17, JAK3 deficiency in 12, RAG1 or RAG2 deficiency in 7, CD3 chain deficiencies in 4, and Artemis deficiency in 2. Thirteen patients had unidentified defects that were inherited in autosomal recessive patterns, and the remaining 3 males had unknown defects.

Informed consent was obtained from the parents of all participants, and all protocols were approved annually by the Duke University Institutional Review Board.

Transplantation

Thirteen of the patients received bone marrow transplants from HLA-identical related donors, and 124 patients received T-cell depleted haploidentical transplants from related donors. Bone marrow donors included parents, siblings, grandparents, and uncles. T-cell depletion was performed via soybean lectin agglutination and sheep erythrocyte rosetting as previously described (4). The mean number of nucleated bone marrow cells given was 2.6 × 108/kg body weight. None of the patients received pretransplant chemotherapeutic conditioning nor posttransplant graft-versus-host disease (GVHD) prophylaxis. Eight of these patients died prior to 100 days posttransplantation, with viral infections (including EBV lymphoproliferative disease in two) being the final causes of death.

Of the remaining patients, 111 (86%) survived, of which 95 developed T-cell function within a year of transplantation. Twelve patients went on to receive further transplantation, while two are maintained on PEG-ADA (30) and two patients underwent successful gene therapy (31).

Genomic DNA Preparation and HLA and KIR Typing

Patient and donor DNA was obtained from peripheral blood mononuclear cells (PBMCs) and EBV-transformed B-cell lines using a DNAeasy kit (Qiagen, Valencia, CA). All posttransplant samples were tested by restriction fragment length polymorphism to ensure host origin. HLA compatibility was initially analyzed by either serologic or molecular sequence-specific oligonucleotide (SSO) typing at the HLA-A, B, C, DR, and DQ loci (One Lambda, Canoga Park, CA). All serologic data were subsequently reconfirmed via SSO typing. High resolution HLA-C data were obtained via DNA sequencing. Inhibitory and activating KIR alleles were analyzed in donors and patients by high-resolution SSO typing (One Lambda, Canoga Park, CA).

Analysis of KIR/HLA Compatibility

Patients were divided into groups dependent on the presence or absence of HLA-Bw4, HLA-C Ser77Asn80 (Group C1), and HLA-C Asn77Lys80 (Group C2). The absence of a KIR ligand in the recipient (Bw4, C1 or C2) for inhibitory KIR present in the donor (KIR3DL1, KIR2DL2/3, KIR2DL1, respectively) was defined as having the potential for a KIR alloreaction. If a donor-inhibitory KIR allele was absent, no alloreaction was defined regardless of the recipient HLA status. Conversely, in order to define possible host-versus-graft KIR alloreactions, host KIR alleles and donor HLA-Bw4 and HLA-C were compared in transplantations where the host possessed natural killer cells.

Laboratory Studies

Lymphocyte proliferation was determined by levels of 3H-thymidine incorporation into patient lymphocytes following stimulation by mitogens phytohemagglutinin (PHA), concavalin A, and pokeweed mitogen. All proliferation assays were run in parallel with identical studies with PBMCs from healthy adult volunteers. Flow cytometry via fluorochrome-conjugated monoclonal antibody staining was used to classify donor and recipient PBMCs using a FACSCalibur (BD Biosciences, San Jose, CA). KIR expression was determined with phycoerythrin-conjugated monoclonal antibodies EB6 (anti-CD158a,h), GL183 (anti-CD158b1/b2,j), and Z27 (anti-CD158e1/e2) (Beckman Coulter, Fullerton, CA). Additional monoclonal antibodies against CD3, CD16, CD56, and CD45 (BD Pharmingen, San Jose, CA) were also utilized.

Statistical Analysis

The primary endpoints measured in this study were T-cell function at 1 year and 5 years, 5-year survival, incidence and severity of graft-versus-host disease, and B-cell function at 1 year and 5 years. T-cell function was determined by lymphocyte proliferation assays, with a PHA stimulation index >100 considered to be normal function. The Kaplan–Meier method was used to determine 5-year survival. GVHD was defined on the 0–4 clinical grading scale (32). B-cell function was determined by measuring immunoglobulin concentrations and antibody titeres to vaccines as well as the requirement for exogenous immunoglobulin therapy.

Risk ratios were used to measure associations between missing KIR ligands and T-cell function, GVHD incidence, and 5-year survival, and were further used to subanalyze groupings by specific missing KIR ligand and by SCID molecular defect. These were created using SAS Ver. 8.2 (SAS Institute, Cary, NC) with the PROC GENMOD procedure (“log” link). Relationships between absence of KIR ligands and immunoglobulin values were calculated using ANOVA through the PROC GLM procedure in SAS Ver. 8.2. Associations between activating and inhibitory KIR pairs and clinical outcomes (GVHD incidence, T-cell function at 1 year, and 5-year survival) were analyzed via the chi-squared statistic in SAS Ver 8.2. All tests were performed at the standard significance level of p < 0.05.

RESULTS

Donor KIR and Recipient HLA Compatibility

Characteristics of recipients with present and missing KIR ligands and donor KIR allele frequencies are listed in Table I and Fig. 1, respectively. Overall, 46 recipients possessed all appropriate HLA alleles for donor KIR, while 91 were missing one or more ligands. It was noted that there were no significant differences in age at transplantation (p = 0.66), total CD34+ cells infused per kilogram body weight (p = 0.24), or total CD3+ cells infused per kilogram body weight (p = 0.18) between the two recipient groups.
Table I.

Patient Characteristics

 

Recipients with present KIR ligands, no. (%)

Recipients with missing KIR ligands, no. (%)

Total

46

91

Molecular defect

  

 X-linked (γc Def)

23 (50)

41 (45)

 JAK3 Def

4 (8.7)

8 (8.8)

 IL-7R alpha Def

4 (8.7)

11 (12.1)

 CD3 chain Def

0

4 (4.4)

 ADA Def

5 (10.9)

12 (13.2)

 RAG1 or RAG2 Def

3 (6.5)

4 (4.4)

 Artemis Def

2 (4.3)

0

 Auto Recessive

3 (6.5)

10 (11)

 Unknown

2 (4.3)

1 (1.1)

Transplant type

  

 HLA Identical

3 (6.5)

10 (11)

 HLA Haploidentical

43 (93.5)

81 (89)

Acute GVHD

  

 Grade 1

15 (33)

27 (29.7)

 Grade ≥2

2 (4.3)

5 (5.5)

T-cell function, 1 year

  

 SI > 100 (PHA)

30/44 (68)

65/90 (72)

 5-year survival

23/34 (68)

63/77 (82)

https://static-content.springer.com/image/art%3A10.1007%2Fs10875-006-9058-7/MediaObjects/10875_2006_9058_Fig1_HTML.gif
Fig. 1.

KIR allele frequencies of the donor population. The majority of donors possess KIR2DL1, KIR2DL3, and KIR3DL1 in their genotype, with 9% missing KIR2DL1 and 6% missing KIR3DL1, precluding possible alloreactions due to lack of HLA-C2 or HLA-Bw4, respectively, in those recipients. No donor was lacking both KIR2DL2 and KIR2DL3.

https://static-content.springer.com/image/art%3A10.1007%2Fs10875-006-9058-7/MediaObjects/10875_2006_9058_Fig2_HTML.gif
Fig. 2.

The effect of the absence of specific inhibitory KIR ligands in recipients on transplantation outcomes. Occurrence of >grade 1 GVHD was similar in groups with present or missing KIR ligands (4.3% and 5.5%, respectively, p = 0.95). HLA and KIR typing were performed by SSO analysis.

KIR Ligand Absence and HCT Outcomes

Analysis of HCT recipients by presence or absence of ligands for donor KIR showed no significant effect on development of T-cell function at one year posttransplantation (n = 135, R2 = 1.05, p = 0.69; Fig. 2 and Table II). Similarly, neither the incidence nor severity of GVHD was affected by host KIR ligand absence (n = 137, R2 = 0.95, p = 0.84), regardless of the specific missing ligand. Analysis of 5-year survival showed that the absence of KIR ligands was associated with a favorable survival effect (Figs. 2 and 3) which did not reach significance in the overall population (n = 111, R2 = 1.21, p = 0.11). Analysis of haploidentical transplants alone showed similar statistically insignificant improvement in 5-year survival (n = 98, R2 = 1.23, p = 0.13), although the exclusion of patients who died prior to 100 days posttransplant diminished this effect (n = 103, R2 = 1.13, p = 0.23). This improvement did not appear to be dependent on any specific missing KIR ligand, nor did any particular ligand produce a significant survival effect.

Further risk ratio analysis of the recipients by KIR ligand status and specific molecular defect similarly showed no statistical difference in clinical outcomes (Table III). Notably, patients who possess defects in γc (representing the majority of the cohort) showed virtually unchanged rates of T-cell function, survival, and GVHD regardless of the presence or absence of KIR ligands.

Analysis of posttransplant IgA and IgM values by ANOVA showed no significant difference between the groups possessing and missing KIR ligands (n = 122, for IgA: p = 0.46; for IgM: p = 0.33, Table IV). Similar results were found when analyzing by transplant type (identical versus haploidentical) (for IgA: p = 0.14; for IgM: p = 0.23), and by specific molecular defect. Interestingly, the recipients with present KIR ligands showed a 27% higher requirement for long-term IVIG therapy than those missing one or more KIR ligands. However, a definite link between missing KIR ligands, IVIG use, and functional B-cell deficiency could not be shown statistically.
Table II.

Missing KIR Ligand Effect on Transplantation Outcomes by Ligand Type

 

Acute GVHD

T-cell function (1 yr)

Five-yr survival

 

n

R2 (95% CI)

p

n

R2 (95% CI)

p

n

R2 (95% CI)

p

Missing HLA-C1a

65

1.40 (0.83–2.35)

0.21

64

1.04 (0.77–1.41)

0.79

50

1.06 (0.80–1.39)

0.69

Missing HLA-C2b

75

0.82 (0.50–1.34)

0.42

73

1.11 (0.90–1.38)

0.33

59

1.16 (0.95–1.42)

0.14

Missing HLA-Bw4

68

0.87 (0.52–1.46)

0.61

67

0.97 (0.77–1.23)

0.81

51

1.12 (0.91–1.37)

0.30

Missing HLA-Bw4 and C2

67

0.87 (0.44–1.71)

0.69

66

1.11 (0.84–1.45)

0.47

53

1.20 (0.96–1.52)

0.12

Overall missing KIR ligand

137

0.95 (0.60–1.52)

0.84

135

1.05 (0.83–1.32)

0.69

111

1.21 (0.96–1.53)

0.11

aHLA-C1 is defined as HLA-C Ser77Asn80.

bHLA-C2 is defined as HLA-C Asn77Lys80.

https://static-content.springer.com/image/art%3A10.1007%2Fs10875-006-9058-7/MediaObjects/10875_2006_9058_Fig3_HTML.gif
Fig. 3.

The effect of the presence or absence of inhibitory KIR ligands in recipients on 5-year survival posttransplant. Percentage survival at each time was determined by the Kaplan–Meier method. Patient survival was reported up to 24.1 years posttransplantation (Median posttransplantation year reporting: 10.3 years). The difference in survival rate based on KIR ligand presence or absence did not reach significance (p = 0.11).

KIR Ligand Effects in Sibling Pairs Following Maternal Haploidentical HCT

In several families with more than one sibling affected with SCID, the same donor was used for bone marrow transplantation for both siblings. Within these pairs (all of whom developed T-cell function within a year of transplantation), the presence or absence of KIR ligands in the recipient did not correspond with improvements in GVHD or development of B-cell function (as determined by sufficient immunoglobulin production to allow discontinuation of IVIG, Table V). The number of mismatched HLA Class I and II antigens in a graft-versus-host direction did not correlate with incidence of GVHD, nor did the number of HLA Class I and II mismatches in a host-versus-graft direction correlate with development of T-cell or B-cell function.

Activating KIR and HCT Outcomes

Donor grouping by allelic activating and inhibitory KIR pairs (specifically, presence of inhibitory KIR2DL1-5 and corresponding activating KIR2DS1-5) and comparison to transplantation outcomes (5-year survival, development of T-cell function, and incidence and severity of GVHD) by chi-squared procedure produced a significant association only with regard to KIR2DS3/KIR2DL3 (p = 0.029). Risk ratio analysis of donor KIR2DS3 and KIR2DL3 status did not show any significant associations with GVHD incidence, T-cell function, or 5-year survival as numbers for the chi-square and risk ratios for the KIR2D3 population were limited (n = 5 for KIR2DS3/KIR2DL3, and n = 7 for KIR2DS3+/KIR2DL3).
Table III.

Missing KIR Ligand Effects on Haploidentical Transplantation by Specific Molecular Defect

 

Acute GVHD

T-cell function (1 yr)

Five-yr survival

 

n

R2 (95% CI)

p

n

R2 (95% CI)

p

n

R2 (95% CI)

p

ADA Def

17

1.67 (0.24–11.45)

0.59

17

0.83 (0.46–1.51)

0.59

16

1.0 (0.52–1.92)

1.00

IL-7RA Def

15

1.09 (0.15–7.69)

0.93

15

0.73 (0.33–1.59)

0.49

12

1.6 (0.39–6.62)

0.39

JAK3 Def

 

NT

 

12

1.75 (0.63–4.83)

0.18

10

0.88 (0.67–1.14)

0.62

X-linked

63

1.09 (0.62–1.93)

0.76

63

1.04 (0.78–1.41)

0.75

52

1.02 (0.76–1.38)

0.89

Table IV.

Effect of KIR Ligand Absence on Maximal IgA/IgM Levels (n = 122)

 

Present KIR ligands mean (mg/dL) ± SD

Missing KIR ligands mean (mg/dL) ± SD

p

Maximal IgA at 1 year posttransplantation

30.8 ± 47.1

97.1 ± 288.9

0.46

Maximal IgM at 1 year posttransplantation

103.5 ± 106.9

187.7 ± 449.5

0.33

Recipient KIR/Donor HLA Effects on T-Cell Function in NK-Positive SCID Patients

Of the 22 recipients with NK+ SCID (IL-7Rα, CD3 chain, RAG1/2, or Artemis deficiency), analysis of donor HLA and recipient KIR showed that six donors had all appropriate KIR ligands, while 18 were missing one or more ligands. No correlation was found between donor KIR ligand absence and failure of development of T-cell function in the recipient (n = 22, R2 = 0.60, p = 0.17). Donor KIR ligand absence also had no effect on incidence of GVHD (n = 20, R2 = 0.81, p = 0.79) or 5-year survival (n = 17, R2 = 1.03, p = 0.94).

DISCUSSION

Studies of KIR alloreactions have shown a beneficial effect on myeloid leukemia following HCT, although additional studies have not yet shown a similar effect in hematopoietic transplantation for other conditions. No previous studies have examined the effect of KIR on marrow transplantation in primary immunodeficiency diseases, and none have focused on transplantation without pretransplant conditioning of any type. Posttransplant GVHD prophylaxis was also used in several studies (23, 24), which may diminish alloreactions.

This study was designed to determine if KIR alloreactivity affects bone marrow stem cell transplantation in SCID infants who received both HLA-identical and haploidentical related donor marrow without pretransplant chemotherapy or posttransplant GVHD prophylaxis. Although KIR and NK reconstitution patterns resembled previous studies of HCT for other conditions, no correlation was found between KIR ligand compatibility and rates of GVHD or development of T-cell function. The lack of correlation persisted regardless of the specific molecular defect producing the SCID phenotype, and additionally was reflected in the outcomes of sibling pairs who underwent haploidentical HCT from the same donor. Although an improvement in 5-year survival approached significance in those lacking KIR ligands, the effect was lessened by exclusion of patients who died prior to 100 days posttransplant. These results strongly suggest that KIR play a very limited role in the setting of HCT for treatment of SCID.

It is possible that the lack of an effect on GVHD may be due to the differences in transplantation procedure, as several publications point out that the tissue damage and inflammation caused by preparative chemotherapy or radiation plays a large role in the initiation of GVHD by host antigen presenting cells(APC) (33, 34). Since pretransplant conditioning was not used in the SCID patients treated here, the depletion of host APCs by alloreactive NK cells may not have an appreciable effect on GVHD possibly because the role of APCs in initiation may be reduced. Further, a recent study showed that production of IFN-γ by matched unrelated donor NK cells correlated strongly with the incidence of GVHD in the posttransplantation period (16), again in a situation where pretransplant conditioning was used. It has been shown that the primary producer of IFN-γ within the NK population is the CD56bright subset, which at baseline, express little or no KIR (35).

Previous studies of interactions between human NK cells and B-cells have yielded mixed results, with some noting in vitro induction of IgG secretion, and others noting no increase in immunoglobulin synthesis with NK stimulation alone (36, 37). It has also been observed that transfer of activated donor NK cells accelerated humoral reconstitution in mice following allogeneic BMT (14). In this study, KIR compatibility did not have a demonstrable effect on IgM or IgA expression, suggesting that there was no impact on B-cell class switching.
Table V.

KIR Effects on Maternal Haploidentical Transplantations into Sibling Pairs

  

Total HLA Ag mismatches

   
 

Molecular defect

GVHa

HVGb

KIR-HLA compatibility

GVHD grade

B-cell function

Family 1

ADA Def

4

5

No missing ligands

0

Yes

  

5

5

Missing HLA-C2

1

Yes

Family 2

X-linked

4

4

Missing HLA-C2

0

No

  

4

5

Missing HLA-C2

1

No

Family 3

IL-7Ra Def

3

3

Missing HLA-C1

1

Yes

  

4

4

No missing ligands

0

Yes

Family 4

X-linked

4

3

Missing HLA-C2

0

No

  

1

1

Missing HLA-C2

0

Yes

Family 5

X-linked

3

3

Missing HLA-C1

0

No

  

4

3

No missing ligands

0

No

Family 6

RAG2 Def

4

4

No missing ligands

0

No

  

3

5

Missing HLA-Bw4

2+

No

aGraft-versus-host MHC antigen mismatch is defined as number of host HLA Class I and II alleles absent in the donor.

bHost-versus-graft MHC antigen mismatch is defined as number of donor HLA Class I and II alleles absent in the host.

It has been shown in the “hybrid resistance” model that natural killer cells can cause rejection of marrow allografts in mice after lethal irradiation, and subsequent work attributed this effect in part to Ly49, a KIR homologue on murine NK cells (5). This study showed no change in GVHD or survival with missing KIR ligands in donors, while a nonsignificant decrease in development of T-cell function at 1-year posttransplantation was seen (n = 22, R2 = 0.60, p = 0.17). Though this limited power study may suggest that increased resistance to engraftment occurs with absence of KIR ligands in donors for the recipient KIR, the lack of impact on 5-year survival (n = 17, R2 = 1.03, p = 0.94) suggests that either this effect is truly insignificant, or that the resulting resistance is not severe enough to influence mortality.

CONCLUSION

This study suggests that KIR alloreactivity neither helps nor hinders HCT for SCID. Accordingly, KIR typing of donors of HCT for SCID does not appear to be clinically useful. It is possible that the inherent differences in the stem cell transplants in this cohort compared to HCT given to leukemia patients, most notably the lack of preconditioning regimens and posttransplant GVHD prophylaxis, may allow other factors to predominate over KIR alloreactivity in affecting clinical outcomes.

We believe that the risks of infection and other serious adverse effects following myeloablative conditioning and immunosuppressive agents given for GVHD prophylaxis far outweigh the risks of graft failure and the relatively low risk of high-grade GVHD following related haploidentical HCT for SCID, particularly given the success rates achieved (1, 3, 4). Whether selection of donors by both KIR genotype and KIR serologic data will yield improved transplantation outcomes in conditions other than myelogenous leukemia is not yet known. Further research, particularly in regard to the relationship between KIR genotype and phenotype, may determine if it will be possible to extend the clinical benefits of KIR alloreactivity to a broader variety of conditions treated by HCT.

Acknowledgments

This research was supported by NIH Grant 5R01-AI/HD042951-07 and the Howard Hughes Medical Institute Research Fellows Program. The authors would like to thank Ms. Adella Clark, Ms. Myriah Cooney, Ms. Donna Oliver, Ms. Roberta Parrott, and Ms. Elisa Sajaroff, for their excellent technical assistance, and Ms. Lora DeRubeis for her administrative work. We would also like to thank Dr. Eric Long, Dr. Sumi Rajagopalan, and Dr. Andreas Velardi for kindly sharing their protocols and advice. We are also grateful to Dr. Peter Parham for his generosity in providing cell lines, and Steven Grambow for his expertise in our statistical analyses.

Copyright information

© Springer Science+Business Media, LLC 2006