Mismatches of Minor Histocompatibility Antigens between HLA-Identical Donors and Recipients and the Development of Graft-Versus-Host Disease after Bone Marrow Transplantation
Els Goulmy, Ph.D., Ronald Schipper, M.Sc., Jos Pool, Els Blokland, J.H., Frederik Falkenburg, M.D., Ph.D., Jaak Vossen, M.D., Ph.D., Alois Gratwohl, M.D., Ph.D., Georgia B. Vogelsang, M.D., Ph.D., Hans C. van Houwelingen, Ph.D., and Jon J. van Rood, M.D., Ph.D.
Background Graft-versus-host disease (GVHD) can be a major complicationof allogeneic bone marrow transplantation even when the donorand recipient are siblings and share identical major histocompatibilityantigens. The explanation may be a mismatch of minor histocompatibilityantigens. We previously characterized five minor histocompatibilityantigens, HA-1, 2, 3, 4, and 5, that are recognized by T cellsin association with the major histocompatibility antigens HLA-A1and A2.
Methods We collected peripheral-blood leukocytes from 148 bonemarrow recipients and their sibling donors, who were genotypicallyHLA identical. Fifty pairs were positive for HLA-A1, 117 werepositive for HLA-A2, and 19 were positive for both. The pairswere typed with cytotoxic-T-cell clones specific for minor histocompatibilityantigens HA-1, 2, 3, 4, and 5.
Results Mismatches of HA-3 were equally distributed among recipientsin whom GVHD developed and those in whom it did not. By contrast,a mismatch of only HA-1 was significantly correlated with GVHDof grade II or higher (odds ratio, ; P = 0.02) in adults. Oneor more mismatches of HA-1, 2, 4, and 5 were also significantlyassociated with GVHD (odds ratio, ; P = 0.006) in adults. Theseassociations were not observed in children.
Conclusions A mismatch of minor histocompatibility antigen HA-1can cause GVHD in adult recipients of allogeneic bone marrowfrom HLA-identical donors. Prospective HA-1 typing may improvedonor selection and identify recipients who are at high riskfor GVHD.
Recipients of allogeneic bone marrow grafts run the risk ofgraft-versus-host disease (GVHD) or graft failure, even whenthe donor and recipient have identical major histocompatibilityantigens and are closely related.1 These complications may arisefrom disparities in minor histocompatibility antigens betweendonor and recipient, with the antigen present in the recipientand not in the donor.2,3 In such cases, T cells in the transplanteddonor marrow respond to minor histocompatibility antigens inthe recipient.
Cytotoxic T lymphocytes directed against minor histocompatibilityantigens of the host have been demonstrated in blood from recipientsof bone marrow from donors who were genotypically HLA identical.4,5,6,7,8,9,10Clones of such cytotoxic T cells have been isolated from lymphocytepopulations in the blood of patients with severe GVHD. Theseclones have been used as reagents to identify five non–sex-linkedminor histocompatibility antigens, designated HA-1, 2, 3, 4,and 5. Most of the cytotoxic-T-cell clones isolated from variouspatients reacted against HA-1.11
For immune recognition, the HA-1, 2, 4, and 5 antigens mustbe presented to cytotoxic T cells by the major histocompatibilityantigen HLA-A2. In this way they behave like antigens recognizedin an HLA-restricted fashion. The HA-1 antigen is present in69 percent of normal people who express HLA-A2, whereas thefrequencies of the three others in this set of HLA-A2–restrictedminor histocompatibility antigens are either high (95 percentfor HA-2) or low (16 percent for HA-4 and 7 percent for HA-5).The HLA-A1–restricted minor histocompatibility antigenHA-3 occurs in 88 percent of persons positive for HLA-A1.11HA-1, 2, 4, and 5 are inherited independently of the HLA genes;each of them is a single gene, and none have a locus withinthe HLA region.12
We investigated whether mismatching of minor histocompatibilityantigens contributes to acute GVHD (grade II or higher) in recipientsof genotypically HLA-identical bone marrow. We collected peripheral-bloodlymphocytes from 148 donor–recipient pairs of siblingswho were positive for HLA-A1 or A2 and who were genotypicallyHLA identical. The lymphocytes from these donor–recipientpairs were analyzed by means of a series of cytotoxic-T-cellclones specific for five well-defined minor histocompatibilityantigens, HA-1, 2, 3, 4, and 5.
Methods
Patients
We studied 148 recipients of bone marrow and their sibling donors,who were genotypically HLA identical, at Leiden University Hospital,Leiden, the Netherlands; Kantonsspital, Basel, Switzerland;and Johns Hopkins Oncology Center, Baltimore. The donor–recipientpairs were selected on the basis of the presence of HLA-A1 orA2 (or both), which are the HLA restriction molecules for minorhistocompatibility antigens HA-3 (HLA-A1) and HA-1, 2, 4, and5 (HLA-A2).11 Fifty pairs were positive for HLA-A1, 117 pairswere positive for HLA-A2, and 19 pairs were positive for both(Table 1). No other exclusion criteria were applied. There were105 pairs of adults and 43 pairs of children (age, <16 years).The recipients underwent bone marrow transplantation between1982 and 1990 for acute lymphocytic leukemia, acute myelocyticleukemia, chronic myelocytic leukemia, non-Hodgkin's lymphoma,or aplastic anemia. Consecutive patients were selected for thestudy. None of the recipients received bone marrow depletedof T cells. As prophylaxis against GVHD, they received methotrexate(51 patients), cyclosporine (80 patients), or both (17 patients);6 patients also received prednisolone. In the assessment ofGVHD, a grade of 0 or I was considered to indicate the absenceof such disease, and a grade of II or higher its presence. Allcases of chronic GVHD occurred in patients with grade II orhigher acute GVHD. The relatively high frequency of GVHD inour study (60.7 percent) is most likely due to the use of methotrexateor cyclosporine as the principal form of prophylaxis.13
Table 1. Status of Major Histocompatibility Antigens in 148 Donor–Recipient Pairs.
Blood Samples
Blood samples were obtained from the patients and their siblingdonors before bone marrow transplantation and treated with heparin.The search for and selection of an HLA-identical sibling donorwere based on HLA typing for the HLA-A, B, and DR antigens ofthe patients' families. Peripheral-blood leukocytes were isolatedby Ficoll–Isopaque density-gradient centrifugation, washed,and resuspended in RPMI-1640 medium with 10 percent dimethylsulfoxide for cryopreservation in liquid nitrogen.
Cytotoxic-T-Cell Clones Specific for HA-1, 2, 3, 4, and 5
The cytotoxic-T-cell clones specific for HA-1, 2, 3, 4, and5 have been described in detail elsewhere.11,14 These cloneswere assayed for their ability to lyse phytohemagglutinin-stimulatedperipheral-blood leukocytes from donors and recipients at variouseffector-to-target ratios. The leukocytes were labeled withchromium-51, and the extent of lysis was measured with a standardchromium-release assay.15 The assays were carried out retrospectivelywithout knowledge of the clinical results. All experiments wererepeated at least twice. A minor histocompatibility antigenwas considered to be present when the percentage of lysis wasat least 25 percent at the lowest effector-to-target ratio (i.e.,1 to 1).
Statistical Analysis
For this analysis of mismatching of minor histocompatibilityantigens and GVHD, we considered a grade of II or higher asindicating the presence of GVHD.16,17 Each donor–recipientpair was categorized as matched or mismatched for each of theminor histocompatibility antigens. When the recipient was positivefor the antigen and the donor was negative, the pair was countedas mismatched. Otherwise the pair was considered to be matched.We obtained maximum-likelihood estimates of the odds ratiosfor the association between match–mismatch status andGVHD, with stratification according to the age (adult or child)of the recipient. These ratios are presented with exact 95 percentconfidence intervals and exact two-sided P values, calculatedwith the Egret statistical package.18 Heterogeneity betweenstrata was evaluated with Zelen's exact test.19 Patients withmissing values were excluded from the analysis of any of theminor histocompatibility antigens for which data were missing.
Results
We typed 148 pairs of bone marrow donors and recipients whowere genotypically HLA identical for HLA-A1 and A2 (Table 1).The HLA-A1–positive donor pairs were typed for HA-3, andthe HLA-A2–positive pairs were typed for HA-1, 2, 4, and5 (Table 2). Male recipients were considered to have H-Y, asex-linked minor histocompatibility antigen, and were calledH-Y–positive; female patients were considered to be H-Y–negative.The results were then evaluated to determine whether they werecorrelated with the development of GVHD after bone marrow transplantation.
Table 2. Status of Minor Histocompatibility Antigens in 50 HLA-A1–Positive and 117 HLA-A2–Positive Donor–Recipient Pairs.
We found no correlation of HA-3–antigen status with GVHD(Table 3). The HA-3–specific cytotoxic T cells we usedto identify HA-3–positive donors and recipients were originallygenerated in a patient with severe acute GVHD. Nevertheless,the typing analysis in HLA-A1–positive pairs revealedan HA-3 mismatch in three patients with GVHD and four patientswith no clinical signs of the disease (Table 3). We also notedthis lack of correlation in our earlier studies.14
Table 3. Results of HA-3 Typing According to GVHD Status in 50 HLA-A1–Positive Donor–Recipient Pairs.
We found no influence of sex discordance in male (H-Y–positive)recipients of bone marrow from female (H-Y–negative) donorson the occurrence of GVHD. The H-Y antigen is influential intransplantation and can lead to graft rejection and GVHD.14Among the HLA-A1–positive pairs mismatched for sex (malerecipient, female donor), the number of recipients with GVHDwas similar to the number without GVHD (six vs. five) (Table 3);similar patterns of distribution were found in HLA-A2–positivemale recipients of bone marrow from female donors (Table 4).
Table 4. Results of HA-1, 2, 4, and 5 Typing and GVHD Status in 117 HLA-A2–Positive Donor–Recipient Pairs.
The effect of mismatches of HA-1, 2, 4, and 5 was studied inHLA-A2–positive pairs (Table 4). Since the numbers ofmismatches for HA-2, 4, and 5 were small, we focused first onthe effect of HA-1 mismatches. There was a significant associationbetween an HA-1 mismatch and GVHD in adults (odds ratio, ; 95percent confidence interval, 1.3 to ; P = 0.02) but not in children(odds ratio, 1.2; 95 percent confidence interval, 0.02 to 26;P =1.00) (Table 5). Zelen's exact test (which measures heterogeneitybetween groups) showed no significant difference between theodds ratios in adults and children. The pooled odds ratio obtainedfrom a stratified analysis was 5.4 (95 percent confidence interval,1.0 to 56; P = 0.05). It was notable that GVHD developed inall 10 cases in which the adult bone marrow recipient was HA-1–positiveand the adult bone marrow donor was HA-1–negative (Table 5).
Table 5. Status of the HA-1 Antigen and GVHD in 115 Donor–Recipient Pairs.
We also analyzed the effect of a mismatch of one or more ofthe minor histocompatibility antigens HA-1, 2, 4, and 5. Weconsidered a mismatch to be present if the donor–recipientpairs were mismatched for at least one of these antigens. Weconsidered a match to be present if the pairs were matched forall four antigens. Of the 115 HLA-A2–positive pairs testedfor HA-1, 17 could not be classified because of missing information.The results for the remaining 98 pairs are shown in Table 6.For the group as a whole there was a significant associationbetween a mismatch and GVHD (odds ratio, 6.4; 95 percent confidenceinterval, 1.4 to 43; P = 0.01). The odds ratio in children was1.9 (95 percent confidence interval, 0.1 to 22; P=0.07), andin adults it was infinite (95 percent confidence interval, 1.8to ; P = 0.006). Again, Zelen's test did not show a significantdifference between the odds ratios in children and adults. Thefinding of a mismatch of more than one of the four antigens(HA-1, 2, 4, and 5) was slightly more predictive of GVHD thanwas the finding of an HA-1 mismatch alone (Table 5). GVHD developedin all 12 adult bone marrow recipients who were positive forat least one of the four antigens and whose donors were negativefor those antigens.
Table 6. Status of the HA-1, 2, 4, and 5 Antigens and GVHD in 98 Donor–Recipient Pairs.
Discussion
Our study demonstrates a significant correlation between mismatchesof minor histocompatibility antigens HA-1, 2, 4, and 5 in HLA-A2–positivedonor–recipient pairs and GVHD. The frequency of the HLA-A2phenotype is 49 percent in the white population. Among the 12adult recipients with a mismatch of these antigens and GVHD,8 had only an HA-1 mismatch; 1 had mismatches of HA-1 and 4,and 1 mismatches of HA-1 and 5; the 2 remaining recipients werematched for HA-1 but mismatched for HA-2 or 5.
The impact of mismatches of minor histocompatibility antigenson the development of GVHD is best studied in pairs of siblingswho are genotypically HLA identical. In such pairs the effectof the disparity would not be overshadowed by unknown mismatchesof major histocompatibility antigens. Siblings discordant forminor histocompatibility antigens are possible only in familiesin which both parents are heterozygotes or one parent is heterozygousand the other homozygous for the minor-histocompatibility-antigenallele.12 A minor histocompatibility antigen is of clinicalinterest only if it is immunogenic and when it has a moderatelyfrequent distribution in the population. Elkins et al.20 failedto demonstrate any influence of mismatching of the minor histocompatibilityantigen W1 on GVHD because the number of W1 mismatches was toolow (i.e., there was a high phenotypic frequency). By contrastthe HA-1 antigen fulfills two of the conditions required forthe induction of GVHD: it is immunogenic and has a moderatephenotypic frequency (69 percent).
Other elements of the immunogenic potency of the HA-1 antigenmust also be considered. For example, a response by cytotoxic-T-cellprecursors that are specific for a minor histocompatibilityantigen requires helper T cells. A large number of helper Tcells, due to cross-reactivity or hyperactivation, might increasethe frequency of cytotoxic-T-cell precursors specific for HA-1.Cross-reactivity of cytotoxic T cells themselves seems unlikelysince, at least in vitro, the recognition of HA-1 is governedsolely by HLA-A2.1, and HA-1 segregates in families in a mendelianfashion.11,12
The distribution of HA-1 in tissue might explain its correlationwith GVHD. HA-1 and HA-2 are expressed only on cells derivedfrom hematopoietic precursors, including dendritic cells andepidermal Langerhans' cells.21,22 Since the chief function ofthe latter cells is to present antigens to T cells, they areplausible candidates for eliciting a graft-versus-host reactionfrom donor T cells. The H-Y and HA-3 antigens occur on hematopoieticand nonhematopoietic cells. In parenchymal tissues of the host,they might induce immune tolerance in antihost cytotoxic T cells.23Such a mechanism can account for the absence of correlationbetween HA-3 and H-Y mismatches and GVHD. However, our resultsfor H-Y are not in line with the report of an increased frequencyof GVHD in male recipients of marrow from female donors.24 Thiseffect was seen primarily with female donors who had been pregnantor received a transfusion,24 but it was not observed in allstudies.25
It has been suggested that GVHD is less frequent in young patientsthan in adult recipients of allogeneic bone marrow.24,25 Almostall of the children in our study were seen at the Departmentof Pediatrics at Leiden University Hospital, where the occurrenceof GVHD is reduced because complete rather than selective decontaminationof the intestinal tract is performed.26 Our data are ambiguouswith respect to the effect of mismatches of minor histocompatibilityantigens on GVHD in children. The odds ratio of GVHD with amismatch of HA-1, 2, 4, or 5 in this group was not significantlydifferent from 1 (odds ratio, 1.9; 95 percent confidence interval,0.1 to 22), but there was no significant difference betweenthe odds ratio in children and the odds ratio in adults (P =0.21 by Zelen's test). This ambiguity is due to the small number(n = 34) of children in the study.
In conclusion, our data demonstrate an association between thepresence of an HA-1 mismatch and the occurrence of GVHD in adultrecipients of bone marrow from genotypically HLA-identical donors.In all cases in which an HA-1–positive patient receivedbone marrow from an HA-1–negative donor, GVHD (grade IIor higher) developed. Of 71 adult donor–recipient pairsmatched for HA-1, 28 of the recipients showed no clinical signsof GVHD. Our results suggest the clinical usefulness of HA-1typing for HLA-A2–positive donor–recipient pairsto identify HLA-A2–positive recipients who are at highrisk for GVHD. The HA-1 cytotoxic-T-cell clones that we usedare available to others for typing. Molecular typing of theseminor histocompatibility antigens may soon be feasible.27,28The HA-2 antigen has already been identified and appears tooriginate from a member of the class I myosin family, a largefamily of proteins involved in cell locomotion and organelletransport.27
Supported by a grant from the J.A. Cohen Institute for Radiopathologyand Radiation Protection.
We are indebted to Mrs. M. Hartog and Mrs. I. Curiël fortyping the manuscript, to Drs. G.M.T. Schreuder, F.H.J. Claas,J. D'Amaro, and M. Oudshoorn for fruitful discussions, and toDr. J. Henwood for critical reading of the manuscript.
Source Information
From the Department of Immunohematology and Blood Bank (E.G., R.S., J.P., E.B.), the Department of Hematology (J.H.F.F.), the Department of Pediatrics (J.V.), the Department of Medical Statistics (H.C.H.), and Europdonor Foundation (J.J.R.), Leiden University Hospital, Leiden, the Netherlands; the Division of Hematology, Department of Research, Kantonsspital, Basel, Switzerland (A.G.); and Johns Hopkins Oncology Center, Baltimore (G.B.V.).
Address reprint requests to Dr. Goulmy at the Department of Immunohematology and Blood Bank, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
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(2004). CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans. Blood
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Harashima, N., Kurihara, K., Utsunomiya, A., Tanosaki, R., Hanabuchi, S., Masuda, M., Ohashi, T., Fukui, F., Hasegawa, A., Masuda, T., Takaue, Y., Okamura, J., Kannagi, M.
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Marijt, W. A. E., Heemskerk, M. H. M., Kloosterboer, F. M., Goulmy, E., Kester, M. G. D., van der Hoorn, M. A. W. G., van Luxemburg-Heys, S. A. P., Hoogeboom, M., Mutis, T., Drijfhout, J. W., van Rood, J. J., Willemze, R., Falkenburg, J. H. F.
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Heslop, H. E., Stevenson, F. K., Molldrem, J. J.
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Choi, E. Y., Christianson, G. J., Yoshimura, Y., Jung, N., Sproule, T. J., Malarkannan, S., Joyce, S., Roopenian, D. C.
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; P = 0.02) in adults. One or more mismatches of HA-1, 2, 4, and 5 were also significantly associated with GVHD (odds ratio, 
