FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 345:1794-1800 December 20, 2001 Number 25 Next

Abstract PDF Supplementary Material Editorial by Rubinstein, P. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Successful engraftment of hematopoietic stem cells from unrelated donors is influenced by disparities between the donor and recipient for HLA-A, B, and C alleles. Disparities between HLA sequence polymorphisms that are serologically detectable are termed antigen mismatches, whereas those that can be identified only by DNA-based typing methods are termed allele mismatches. Whether both kinds of polymorphisms are important in transplantation is not known. We tested the hypothesis that allele mismatches that are detectable only at the DNA level are less immunogenic than those that are serologically detectable and thereby are associated with a lower risk of graft failure after hematopoietic-cell transplantation.

Methods We used DNA sequencing to define the HLA-A, B, and C alleles in 471 patients who received bone marrow from unrelated donors for the treatment of chronic myeloid leukemia after myeloablative conditioning therapy. The odds ratios for graft failure were determined for recipients of transplants from donors with a single class I allele mismatch, a single class I antigen mismatch, or two or more class I mismatches, as compared with those with no mismatch.

Results A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk. The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches.

Conclusions HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure.

A hallmark of HLA alleles is their extraordinary diversity.¹⁰ Alleles encoding HLA molecules that are recognized by alloantibodies induced by pregnancy or transfusions have been identified as HLA antigens. Any given HLA antigen may be encoded by a family of HLA alleles with similar nucleotide sequences. Different alleles encoding the same antigen can be distinguished only by DNA-based typing methods. Transplant donor and recipient pairs with different HLA antigens always have different alleles (and are referred to as "antigen mismatched") (Table 1), and pairs with the same allele always have the same antigen ("matched"). Some donors and recipients with the same HLA antigen have different alleles ("allele mismatched"). With few exceptions, HLA allele mismatches are characterized by amino acid substitutions in the regions of the HLA molecule that bind peptides for presentation to T cells, whereas HLA antigen mismatches are characterized by amino acid substitutions relevant to both peptide binding and contact with T cells.^11,12,13,14

View this table: [in this window] [in a new window]   Table 1. Terminology for Donor Matching of HLA Class I Alleles and Antigens.

 
We tested the hypothesis that mismatches for the HLA-A, B, and C alleles are less immunogenic than antigen mismatches and are thereby associated with a lower risk of graft failure after transplantation of marrow from unrelated donors.

Methods

Study Population

A total of 548 patients who were prepared for transplantation with cyclophosphamide and total-body irradiation, underwent transplantation of bone marrow from unrelated donors for treatment of chronic myeloid leukemia, and survived beyond day 28 after transplantation were eligible for the study. Methotrexate and cyclosporine were administered for the prevention of graft-versus-host disease, and T cells were not removed from the donor marrow. A total of 471 donor–recipient pairs for which DNA or lymphoblastoid cell lines were available for retrospective class I and DPB1 sequencing were included in the analysis. Transplantations were performed between May 1985 and October 2000. The study was approved by the institutional review board, and written informed consent was obtained from all patients.

Histocompatibility Testing and Criteria for Selection of Donors

Before transplantation, HLA-A and HLA-B antigens of the donor and the recipient were typed by the standard National Institutes of Health two-stage complement-dependent microcytotoxicity test, and HLA-DR and DQ antigens were typed with the use of purified B cells in a microcytotoxicity assay.^15,16 Before 1991, donor selection was based on matching for HLA-A, B, DR, and Dw.¹⁷ After 1991, HLA-DRB1 allele typing was begun, and a single DRB1 allele mismatch was allowed for patients less than 36 years of age if a matched donor could not be identified.¹⁸ In 1992, we began to use DQB1 allele typing and matching¹⁹ for selection of donors and allowed a single DRB1 or DQB1 mismatch when a matched donor was not available. HLA-C serologic typing was used to select HLA-C–matched donors beginning in 1996, and matches were given priority over mismatches.⁷ All donors had a negative lymphocytotoxic crossmatch before transplantation.

For this study, we sequenced HLA-A, B, C, and DPB1 alleles.^9,20 HLA-A, B, and C mismatches were defined as the presence of donor antigens or alleles not shared by the recipient. Antigen mismatches were detectable by serologic methods, whereas allele mismatches were detectable only by sequencing methods.^10,21 Recipient homozygosity at a mismatched locus was defined as the presence of a single allele.

Transplantation Procedure

All recipients were prepared for transplantation with intravenous cyclophosphamide (60 mg per kilogram of body weight), administered on each of two successive days, followed by total-body irradiation (1200 to 1575 cGy in 6 to 14 fractions). All protocols were reviewed and approved by the institutional review board at the center. Patients were assessed for engraftment if they survived beyond 28 days after infusion of bone marrow from an unrelated donor. Graft failure was defined as failure of the absolute neutrophil count to surpass 500 per cubic millimeter before relapse, second transplantation, or death (primary graft failure); a decrease in the absolute neutrophil count to less than 100 per cubic millimeter on at least three consecutive determinations at least one day apart after the initial engraftment without recovery before relapse, second transplantation, or death (secondary graft failure); or the absence of donor T cells as determined by testing for chimerism with the use of variable-number tandem-repeat polymorphisms or in situ hybridization.⁷

Statistical Analysis

The primary end point of this study was graft failure, and survival was a secondary end point. Odds ratios for the probability of graft failure among class I mismatch categories were estimated with the use of conditional maximum-likelihood estimates from exact logistic regression, and P values were derived from Fisher's exact test. Survival percentages were estimated by the Kaplan–Meier method.²² Comparisons of survival in each of the mismatched groups with survival in the matched group were based on the log-rank test. Variables previously shown to be associated with graft failure and other patient characteristics^7,9,23 were evaluated in each of the class I mismatch categories and compared with the use of the Kruskal–Wallis test for continuous variables and the chi-square test for categorical variables.

Results

Characteristics of the Study Population

Of the 471 donor–recipient pairs, 280 were matched for all six class I alleles, 49 had a mismatch for a single class I allele (16 HLA-A, 17 HLA-B, and 16 HLA-C), 56 had a single mismatch for a class I antigen (23 HLA-A, 4 HLA-B, and 29 HLA-C), and 86 had two or more mismatches for class I alleles or antigens in any combination (Table 2). Of the 105 pairs with a single class I mismatch, 86 (82 percent) were mismatched at HLA-DRB1, DQB1, or DPB1 as revealed by DNA typing. Primary graft failure was diagnosed in 26 patients, and secondary graft failure in 2 patients. In two patients, graft failure was diagnosed by the absence of donor T cells and granulocytes on routine follow-up examination one year after transplantation.

View this table: [in this window] [in a new window]   Table 2. Characteristics of the Study Population.

 
Effect of Recipient Homozygosity on the Risk of Graft Failure

Two graft failures occurred among the 280 transplants matched for HLA-A, B, and C (0.7 percent). Among the 105 pairs mismatched for one class I allele or antigen, 7 recipients were homozygous and 98 were heterozygous at the mismatched locus (Table 3). Among pairs mismatched for a single allele, graft failure occurred in 1 of 2 homozygous recipients and in none of 47 heterozygous recipients (P=0.04). Among pairs mismatched for a single antigen, graft failure occurred in 4 of 5 homozygous recipients and in 7 of 51 heterozygous recipients (P=0.004). Recipient homozygosity for alleles or antigens was significantly associated with graft failure among patients with a single class I mismatch (P<0.001).

View this table: [in this window] [in a new window]   Table 3. Effect of Recipient Homozygosity on the Risk of Graft Failure in Transplants with Single Class I Mismatches.

 
The effect of recipient homozygosity was also evaluated in the 86 transplants with multiple class I allele and antigen mismatches in any combination. Among recipients who were homozygous at any HLA class I locus mismatched for two or three alleles, the proportions of graft failures were one of six and two of four, respectively. Among recipients who were heterozygous at all HLA class I loci mismatched for two, three, four, or five alleles, the proportions of graft failures were 8 of 47, 4 of 22, 1 of 4, and 0 of 3, respectively.

Effects of Allele and Antigen Mismatches on the Risk of Graft Failure

The risk of graft failure conferred by mismatches for HLA-A, B, and C alleles or antigens was measured in heterozygous recipients with a single mismatch (Table 4). Graft failure occurred in none of 47 recipients with donors who were mismatched for a single allele and in 7 of 51 recipients with donors mismatched for a single antigen (14 percent, P=0.01). Among the 76 heterozygous pairs with multiple class I mismatches, 9 donors were mismatched for two or more alleles but no antigens and 67 were mismatched for at least one antigen. Graft failure occurred in 2 of 9 pairs with no antigen mismatching (22 percent) and in 11 of 67 pairs with antigen mismatching (16 percent).

View this table: [in this window] [in a new window]   Table 4. Proportion of Heterozygous Recipients with Graft Failures.

 
In univariate logistic-regression analysis, the odds ratio for graft failure was influenced by the nature and number of mismatches at HLA-A, B, and C (Table 4). Mismatching involving a single HLA-A, B, or C allele was not associated with graft failure. Mismatching involving a single HLA-A, B, or C antigen, multiple HLA class I alleles, or multiple alleles and antigens was associated with an increased risk of graft failure (Table 4).

Previous studies have identified a low dose of marrow cells to be a risk factor for graft failure.^7,9,23 There was a suggestive difference in the dose of marrow cells among the groups categorized in Table 2 (P=0.07). The group with the lowest cell dose, however, consisted of patients matched for all six class I alleles (lowest risk of graft failure). Other factors potentially associated with the risk of graft failure include the number of mismatched HLA class II alleles, the stage of disease at the time of transplantation, and the dose of total-body radiation. The distribution of mismatched class II alleles was not significantly different among the groups with mismatches categorized in Table 2 (P=0.32), nor was the distribution of disease stage (P=0.28). By protocol design, patients with class I mismatches were more likely to have received a higher dose of radiation. The odds ratio for the association between class I mismatching and graft failure was not significantly altered by the presence of HLA-DRB1, DQB1, or DPB1 disparity, the dose of total-body radiation, the dose of marrow cells, or the phase of disease.

Survival at five years for heterozygous recipients with matched donors, donors mismatched for a single class I allele, donors mismatched for a single class I antigen, and donors with multiple class I mismatches and for homozygous recipients with donors mismatched for a single class I allele or antigen was 62 percent, 49 percent, 53 percent, 44 percent, and 43 percent, respectively. Comparison of survival in each of the groups with mismatching with survival in the group with matching of alleles yielded P=0.17 for single allele mismatches, P=0.33 for single antigen mismatches, P=0.002 for multiple mismatches, and P=0.34 for homozygous recipients. Of the 30 patients with graft failure, 6 had recovery of autologous hematopoiesis and are alive. Two patients received reinfusion of cryopreserved autologous stem cells, and both are alive. Nine patients died before a second transplantation could be attempted. Thirteen patients received a second allogeneic transplantation, and seven of them are alive.

Comparison of Amino Acid Substitutions in Patients with Allele or Antigen Mismatches

Figure 1 illustrates the number and position of amino acid substitutions among the heterozygous patients mismatched for a single allele or a single antigen. The single allele mismatches were characterized by 0 to 8 nonsynonymous substitutions in the ₁ domain and by 0 to 9 substitutions in the ₂ domain (total range, 1 to 14; median, 2). The single antigen mismatches encoded 0 to 13 substitutions in the ₁ domain and 0 to 16 in the ₂ domain (total range, 1 to 27; median, 13). The allele and antigen mismatches differed not only in the number of nonsynonymous substitutions but also in the location of the mismatches in the two domains (Figure 1 and Supplementary Appendix 1, available with the full text of this article at http://www.nejm.org).

View larger version (58K): [in this window] [in a new window]   Figure 1. Number and Location of Mismatched Residues Encoded by Single Allele and Single Antigen Mismatches in the Study Population. Panels A and B show the three-dimensional structure of the HLA class I molecule, depicting mismatched residues among the donor–recipient pairs who were mismatched for a single allele (Panel A) and a single antigen (Panel B). Residues are numbered according to their sequence in the protein. Residues involved in peptide binding are shown in dark blue for disparities in the -pleated sheet and light blue for disparities in helixes. Residues implicated in contact with the T-cell receptor are red. Mismatched residues that are not implicated in either peptide binding or T-cell–receptor contact are white; residues involved in both peptide binding and T-cell–receptor contact are gray. Panels C and D show the number of mismatched residues involved in peptide binding and T-cell–receptor contact in each donor–recipient pair mismatched for a single allele (Panel C) and in each pair mismatched for a single antigen (Panel D). Recipients who had graft failure are indicated in dark gray in Panel D. Data for one transplant recipient who did not have graft failure are not included in Panel D because insufficient DNA precluded sequencing of the mismatched HLA-B38 and B39 alleles.

 
Discussion

Graft failure remains a dangerous complication after transplantation of hematopoietic cells from unrelated donors.^9,24,25,26 Our analysis demonstrates that both qualitative and quantitative characteristics of disparity for HLA class I alleles and antigens can be used to categorize the risk of graft failure after transplantation of stem cells from unrelated donors for treatment of chronic myeloid leukemia with myeloablative preconditioning. Furthermore, homozygosity of the recipient was identified as a risk factor for graft failure.

Serologic reagents for the HLA-C locus have been difficult to obtain, possibly because the expression of HLA-C on the cell surface is low as compared with the expression of HLA-A and B antigens.^27,28 In this study, we used DNA sequencing to define HLA-C alleles, and this information was then mapped to standardized, serologically defined antigens.²¹ The relation between HLA-C antigen and allele mismatches and the risk of graft failure followed the pattern observed with HLA-A and B antigen and allele mismatches. These observations indicate that identical criteria can be used to distinguish functionally important epitopes encoded by all three class I genes.

The identification of recipient homozygosity for HLA alleles or antigens as a risk factor for graft failure confirms and extends previous experience with haploidentical grafts from related donors.²⁹ Recipient class I disparity might induce an antirecipient T-cell cytotoxic response in the donor's cells, thereby eliminating any recipient cells that could cause graft failure. From a practical standpoint, if donor mismatches cannot be avoided, then the preferred HLA-A, B, or C allele or antigen mismatch should be at a locus for which the recipient is heterozygous, thereby ensuring a concomitant recipient mismatch to counterbalance the donor mismatch.

The T cells of the recipient cause graft rejection when they are activated by the class I alloantigens of the donor. Natural killer cells in the recipient can cause graft rejection when inhibition of their activation by class I molecules on donor cells is absent.³⁰ Among pairs mismatched at a single locus in our study, nine recipients had homozygous donors, and all had engraftment. These results do not support the hypothesis that the recipient's natural killer cells caused graft failure under the conditions we used for transplantation. Similarly, the high risk of graft failure among homozygous recipients with heterozygous donors indicates that the donor's natural killer cells could not prevent graft failure.

The distribution of substitutions in the coding sequences of HLA-A, B, and C alleles is not random.³¹ Nearly all substitutions involve a change in the amino acid residues that influence binding of peptides in the internal groove or contact of the T-cell receptor with the external helix of the class I molecule.^{11,12,13,14,32} The donor–recipient pairs that were mismatched for a single allele had 0 to 11 substitutions in the residues involved in peptide binding (median, 2) and 0 to 1 substitutions in residues involved in contact with the T-cell receptor (median, 0). The group with a single antigen mismatch had 0 to 16 substitutions in the residues involved in peptide binding (median, 8) and 0 to 9 substitutions in residues involved in contact with the T-cell receptor (median, 1). The allele-mismatch and antigen-mismatch groups differ significantly with respect to the median number of mismatches both for residues involved in peptide binding and for residues involved in T-cell–receptor contact (P<0.001) (Figure 1 and Supplementary Appendix 1).

The seven grafts with single antigen mismatches that failed were mismatched for 5 to 16 residues implicated in peptide binding and for 0 to 9 residues involved in T-cell–receptor contact (Figure 1D). These data demonstrate that T cells are sensitive to qualitative differences between donor and recipient class I molecules, which are defined by the substituted amino acids and their location, and to quantitative differences in the total number of mismatches. These differences together define permissible and nonpermissible HLA disparities in transplantation. The data further suggest that multiple nonsynonymous substitutions affecting peptide binding and T-cell–receptor contact were instrumental in augmenting the strength and breadth of T-cell responses that caused graft failure.³³ We hypothesize that multiple allele mismatches may provide the threshold of disparity needed to activate a similarly strong and broad T-cell response leading to graft failure, an effect that is limiting in single allele mismatches.

The function of an HLA molecule is an extension of its structure. The results of this study demonstrate that class I epitopes capable of generating a humoral response are also involved in the T-cell–mediated cytotoxic responses that cause graft failure. A new definition of acceptable HLA mismatches that is based on functional epitopes may broaden the application of transplantation and provide a means for improving the overall success of transplantation as a curative procedure for hematologic cancers.

Supported by grants from the National Institutes of Health (CA18029, CA72978, CA15704, and AI33484).

We are indebted to Michael Bunce for an independent review of data on HLA-C typing.

Source Information

From the Fred Hutchinson Cancer Research Center (E.W.P., J.A.H., P.J.M., A.W., M.M., T.G., B.S., E.M., C.A.), the University of Washington School of Medicine (E.W.P., J.A.H., P.J.M., A.W., C.A.), and the Seattle Cancer Care Alliance (A.S.) — all in Seattle.

Address reprint requests to Dr. Petersdorf at the Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, or at epetersd{at}fhcrc.org.

References

1. Klein J, Sato A. The HLA system. N Engl J Med 2000;343:702-9, 782. [Erratum, N Engl J Med 2000;343:1504.] [Free Full Text]
2. Opelz G, Wujciak T. The influence of HLA compatibility on graft survival after heart transplantation. N Engl J Med 1994;330:816-819. [Free Full Text]
3. Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med 2000;343:1078-1084. [Free Full Text]
4. Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 1989;320:197-204. [Abstract]
5. Fleischhauer K, Kernan NA, O'Reilly RJ, Dupont B, Yang SY. Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44. N Engl J Med 1990;323:1818-1822. [Medline]
6. Beatty PG, Hansen JA, Longton GM, et al. Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies. Transplantation 1991;51:443-447. [Web of Science][Medline]
7. Petersdorf EW, Longton GM, Anasetti C, et al. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood 1997;89:1818-1823. [Free Full Text]
8. Anasetti C, Hansen JA. Effect of HLA incompatibility in marrow transplantation from unrelated and HLA-mismatched related donors. Transfus Sci 1994;15:221-230. [CrossRef][Medline]
9. Petersdorf EW, Gooley TA, Anasetti C, et al. Optimizing outcomeafter unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 1998;92:3515-3520. [Free Full Text]
10. Marsh SGE, Bodmer JG, Albert ED, et al. Nomenclature for factors of the HLA system, 2000. Tissue Antigens 2001;57:236-283. [CrossRef][Medline]
11. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987;329:506-512. [CrossRef][Medline]
12. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 1987;329:512-518. [CrossRef][Medline]
13. Rammensee HG, Falk K, Rotzschke O. Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 1993;11:213-244. [CrossRef][Web of Science][Medline]
14. Engelhard VH. Structure of peptides associated with class I and class II MHC molecules. Annu Rev Immunol 1994;12:181-207. [CrossRef][Web of Science][Medline]
15. Dausset J, Nenna A. Présence d'une leuco-agglutinine dans le sérum d'un cas d'agranulocytose chronique. C R Soc Biol 1954;146:1539-41.
16. van Rood JJ, van Leeuwen A. Leukocyte grouping: a method and its application. J Clin Invest 1963;42:1382-1390.
17. Dupont B, Braun DW Jr, Yunis EJ, Carpenter CB. HLA-D by cellular typing. In: Terasaki PI, ed. Histocompatibility testing 1980. Los Angeles: UCLA Tissue Typing Laboratory, 1980:229-67.
18. Petersdorf EW, Longton GM, Anasetti C, et al. The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. Blood 1995;86:1606-1613. [Free Full Text]
19. Petersdorf EW, Longton GM, Anasetti C, et al. Definition of HLA-DQ as a transplantation antigen. Proc Natl Acad Sci U S A 1996;93:15358-15363. [Free Full Text]
20. Petersdorf EW, Gooley T, Malkki M, et al. The biological significance of HLA-DP gene variation in haematopoietic cell transplantation. Br J Haematol 2001;112:988-994. [CrossRef][Medline]
21. Schreuder GMT, Hurley CK, Marsh SGE, et al. The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens. Hum Immunol 1999;60:1157-1181. [Medline]
22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
23. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 1998;338:962-968. [Free Full Text]
24. Kernan NA, Flomenberg N, Dupont B, O'Reilly RJ. Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia: identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation 1987;43:842-847. [Web of Science][Medline]
25. McGlave PB, Shu XO, Wen W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program. Blood 2000;95:2219-2225. [Free Full Text]
26. Davies SM, Kollman C, Anasetti C, et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program. Blood 2000;96:4096-4102. [Free Full Text]
27. Bunce M, Vilches C, Marsh SGE, et al. All HLA-C alleles. In: Charron D, ed. Genetic diversity of HLA functional and medical implication. Vol. 1. Paris: EDK, 1997:83-8.
28. Neisig A, Melief CJ, Neefjes J. Reduced cell surface expression of HLA-C molecules correlates with restricted peptide binding and stable TAP interaction. J Immunol 1998;160:171-179. [Free Full Text]
29. Anasetti C. Hematopoietic cell transplantation from HLA partially matched related donors. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic cell transplantation. 2nd ed. Malden, Mass.: Blackwell Science, 1999:904-14.
30. Valiante N, Parham P. Natural killer cells, HLA class I molecules, and marrow transplantation. Biol Blood Marrow Transplant 1997;3:229-235. [Medline]
31. Parham P, Adams EJ, Arnett KL. The origins of HLA-A,B,C polymorphism. Immunol Rev 1995;143:141-180. [CrossRef][Web of Science][Medline]
32. Garboczi DN, Ghosh P, Utz U, Fan QR, Biddison WE, Wiley DC. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 1996;384:134-141. [CrossRef][Medline]
33. Parham P, Ohta T. Population biology of antigen presentation by MHC class I molecules. Science 1996;272:67-74. [Abstract]

Abstract PDF Supplementary Material Editorial by Rubinstein, P. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Arora, M., Weisdorf, D. J., Spellman, S. R., Haagenson, M. D., Klein, J. P., Hurley, C. K., Selby, G. B., Antin, J. H., Kernan, N. A., Kollman, C., Nademanee, A., McGlave, P., Horowitz, M. M., Petersdorf, E. W. (2009). HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia. JCO 27: 1644-1652 [Abstract] [Full Text]  
• Griffith, B. P., Haddad, M., Poston, R. S. (2008). Immunobiology of Heart and Heart-Lung Transplantation. Card Surg Adult 3: 1513-1538 [Full Text]  
• Kawase, T., Morishima, Y., Matsuo, K., Kashiwase, K., Inoko, H., Saji, H., Kato, S., Juji, T., Kodera, Y., Sasazuki, T., for The Japan Marrow Donor Program, (2007). High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood 110: 2235-2241 [Abstract] [Full Text]  
• Devetten, M, Armitage, J. (2007). Hematopoietic cell transplantation: progress and obstacles. Ann Oncol 18: 1450-1456 [Abstract] [Full Text]  
• Wehler, T. C., Nonn, M., Brandt, B., Britten, C. M., Grone, M., Todorova, M., Link, I., Khan, S. A., Meyer, R. G., Huber, C., Hartwig, U. F., Herr, W. (2007). Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 109: 365-373 [Abstract] [Full Text]  
• Guo, Z., Hood, L., Malkki, M., Petersdorf, E. W. (2006). Long-range multilocus haplotype phasing of the MHC. Proc. Natl. Acad. Sci. USA 103: 6964-6969 [Abstract] [Full Text]  
• Chohan, B., Lavreys, L., Rainwater, S. M. J., Overbaugh, J. (2005). Evidence for Frequent Reinfection with Human Immunodeficiency Virus Type 1 of a Different Subtype. J. Virol. 79: 10701-10708 [Abstract] [Full Text]  
• Beelen, D. W., Ottinger, H. D., Ferencik, S., Elmaagacli, A. H., Peceny, R., Trenschel, R., Grosse-Wilde, H. (2005). Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 105: 2594-2600 [Abstract] [Full Text]  
• Petersdorf, E. W., Anasetti, C., Martin, P. J., Gooley, T., Radich, J., Malkki, M., Woolfrey, A., Smith, A., Mickelson, E., Hansen, J. A. (2004). Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood 104: 2976-2980 [Abstract] [Full Text]  
• Flomenberg, N., Baxter-Lowe, L. A., Confer, D., Fernandez-Vina, M., Filipovich, A., Horowitz, M., Hurley, C., Kollman, C., Anasetti, C., Noreen, H., Begovich, A., Hildebrand, W., Petersdorf, E., Schmeckpeper, B., Setterholm, M., Trachtenberg, E., Williams, T., Yunis, E., Weisdorf, D. (2004). Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 104: 1923-1930 [Abstract] [Full Text]  
• Boeckh, M., Nichols, W. G. (2004). The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103: 2003-2008 [Abstract] [Full Text]  
• Cao, T. M., Lo, B., Ranheim, E. A., Grumet, F. C., Shizuru, J. A. (2003). Variable hematopoietic graft rejection and graft-versus-host disease in MHC-matched strains of mice. Proc. Natl. Acad. Sci. USA 100: 11571-11576 [Abstract] [Full Text]  
• Griffith, B. P., Poston, R. S. (2003). Immunobiology of Heart and Heart-Lung Transplantation. Card Surg Adult 2: 1403-1426 [Full Text]  
• Barrett, A. J., Rezvani, K., Solomon, S., Dickinson, A. M., Wang, X. N., Stark, G., Cullup, H., Jarvis, M., Middleton, P. G., Chao, N. (2003). New Developments in Allotransplant Immunology. ASH Education Book 2003: 350-371 [Abstract] [Full Text]  
• Deeg, H. J., Storer, B., Slattery, J. T., Anasetti, C., Doney, K. C., Hansen, J. A., Kiem, H.-P., Martin, P. J., Petersdorf, E., Radich, J. P., Sanders, J. E., Shulman, H. M., Warren, E. H., Witherspoon, R. P., Bryant, E. M., Chauncey, T. R., Getzendaner, L., Storb, R., Appelbaum, F. R. (2002). Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100: 1201-1207 [Abstract] [Full Text]  
• Cooper, D. L., Petersdorf, E. W., Hansen, J. A., Anasetti, C. (2002). HLA Matching for Hematopoietic Stem-Cell Transplants. NEJM 346: 1251-1252 [Full Text]  
• Walters, M. C., Nienhuis, A. W., Vichinsky, E. (2002). Novel Therapeutic Approaches in Sickle Cell Disease. ASH Education Book 2002: 10-34 [Abstract] [Full Text]  
• Hoelzer, D., Gokbuget, N., Ottmann, O., Pui, C.-H., Relling, M. V., Appelbaum, F. R., van Dongen, J. J.M., Szczepanski, T. (2002). Acute Lymphoblastic Leukemia. ASH Education Book 2002: 162-192 [Abstract] [Full Text]  
• Rubinstein, P. (2001). HLA Matching for Bone Marrow Transplantation -- How Much Is Enough?. NEJM 345: 1842-1844 [Full Text]