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TAP1, TAP2, LMP2, DMA, and DMB Genetic Polymorphisms in Renal Transplantation
TAP1, TAP2, LMP2, DMA, and DMB Genetic Polymorphisms in Renal Transplantation T. Kobayashi, I. Yokoyama, S. Hayashi, M. Negita, Y. Namil, A. Katayama, T. Nagasaka, C. Koike, Y. Tachi, G-L. Mei, T. Haba, Y. Tominaga, T. Naruse, H. Inoko, K. Uchida, and H. Takagi
T
HE MAJOR histocompatibility complex-encoded peptide transporters associated with antigen processing (TAP1 and TAP2) and low molecular mass (weight) polypeptides (LMP2 and LMP7) are involved in MHC class I antigen-mediated processing and presentation.1,2 The products of the TAP1 and TAP2 genes form a heterodimeric complex that facilitates transportation of the endogenous peptides into the endoplasmic reticulum, where they associate with MHC class I molecules.1 The proteasomal subunits, LMP2 and LMP7, are believed to conduct in the proteolytic processing of cytosolic and nucleic proteins,2 followed by the translocation of these antigenic peptides by the TAP transporter. HLA-DM (DMA and DMB) has been reported as a critical regulatory molecule in the pathway of class II antigen-restricted antigen processing and presentation to CD41 T lymphocytes.3,4 The DM molecules are involved in the removal of the class II-associated invariant chain peptide and the facilitation of loading with antigen peptides. The TAP1, TAP2, LMP2, DMA, and DMB genes are located between the HLA-DQ and -DP subregions, and
their polymorphisms have been reported.5– 8 The class I and II mediated antigen presentation, which plays an important role in allorecognition after transplantation, may be functionally associated with their genetic polymorphisms. The purpose of this study is to examine whether TAP1, TAP2, LMP2, DMA, and DMB genetic polymorphisms are related to acute rejection after transplantation. We studied a selected population of 50 pairs of donors and recipients who underwent living-related renal transplantation at the Nagoya Daini Red Cross Hospital, the Kakegawa City Hospital, the Yokkaichi City Hospital, and From the Department of Surgery II, Nagoya University School of Medicine and the Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, and the Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan. This study was partly supported by Aichi Kidney Foundation. Address reprint requests to T. Kobayashi, MD, Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466, Japan.
Table 1. Phenotype Frequencies of TAP1, TAP2, LMP2, DMA, and DMB Alleles in Rejection-Free and Rejection (Steroid-Resistant) Groups After Renal Transplantation Recipient
Donor
Rejection (2) (N 5 25)
Rejection (1) (N 5 25)
TAP1*0101 *0201
24 (96%) 9 (36%)
25 (100%) 9 (36%)
24 (96%) 6 (24%)
24 (96%) 7 (28%)
TAP2*0101 *0102 *0103 *0201
17 (68%) 4 (16%) 7 (28%) 11 (44%)b
12 (48%) 6 (24%) 6 (24%) 18 (72%)b
15 (60%) 5 (20%) 12 (48%)a 13 (52%)
19 (76%) 3 (12%) 3 (12%)a 17 (68%)
LMP2-R -H
23 (92%) 12 (48%)
24 (96%) 10 (40%)
21 (84%) 13 (52%)
23 (92%) 13 (52%)
DMA*0101 *0102
24 (96%) 6 (24%)
25 (100%) 6 (24%)
25 (100%) 5 (20%)
24 (96%) 6 (24%)
DMB*0101 *0102 *0103
15 (60%) 13 (52%) 13 (52%)
17 (68%) 13 (52%) 10 (40%)
19 (76%) 11 (44%) 14 (56%)
19 (76%) 12 (48%) 10 (40%)
a b
Rejection (2) (N 5 25)
Rejection (1) (N 5 25)
x2 5 7.714, P 5 .0055, Pc 5 0.022. x2 5 4.023, P 5 .0449, Pc 5 0.1796.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 29–30 (1998)
0041-1345/98/$19.00 PII S0041-1345(97)01170-6 29
30
the Nagoya University Hospital between September 1989 and May 1997. Fifty pairs consisted of a rejection-free group (25 pairs) and a steroid-resistant rejection group (25 pairs). To standardize the effect of HLA matching, all selected pairs possess one HLA haplotype-identical and one DRB1-mismatched combinations. The polymorphisms of the TAP1, TAP2, LMP2, DMA, and DMB genes were analyzed by PCR-RFLP.5– 8 As shown in Table 1, the frequency of TAP2*0103 was significantly increased in donors of the rejection-free group compared to those of the steroid-resistant rejection group (x2 5 7.714, P 5 .0055, Pc 5 0.022). The frequency of TAP2*0201 was considerably higher in recipients of the steroid-resistant rejection group compared to those of the rejection-free group (x2 5 4.023, P 5 .0449, Pc 5 0.1796). There was no significant difference in the allelic frequency of TAP1, LMP2, DMA, or DMB between the rejection-free and steroid-resistant rejection groups. Although it is now difficult to speculate how genetic polymorphisms in the TAP region might influence the allorecognition as a cause of rejection, our results suggest that allelic variation of the TAP2 gene may be associated with the efficiency of donor
KOBAYASHI, YOKOYAMA, HAYASHI ET AL
class I-mediated antigen presentation to recipient T lymphocytes after transplantation. ACKNOWLEDGMENTS We express our appreciation to Hiromi Kamura and Setsuko Kohara, Laboratory for Histocompatibility, Nagoya Daini Red Cross Hospital, and Tomoko Kondo, Department of Surgery II, Nagoya University School of Medicine for excellent technical assistance.
REFERENCES 1. Spies T, Cerundolo V, Colonna M, et al: Nature 355:644, 1992 2. Glynne R, Powis SH, Bech S, et al: Nature 353:357, 1991 3. Morris P, Shaman J, Attaya M, et al: Nature 368:551, 1994 4. Fling SP, Arp B, Pious D: Nature 368:554, 1994 5. Ishihara M, Ohno S, Mlzuki N, et al: Hum Immunol 45:105, 1996 6. Ishihara M, Onho S, Ishida T, et al: Tissue Antigens 49:107, 1997 7. Naruse TK, Kawata H, Ishihara M, et al: Tissue Antigens 47:530, 1997 8. Ishihara M, Naruse T, Ohno S, et al: Hum Immunol 49:144, 1996
T
HE MAJOR histocompatibility complex-encoded peptide transporters associated with antigen processing (TAP1 and TAP2) and low molecular mass (weight) polypeptides (LMP2 and LMP7) are involved in MHC class I antigen-mediated processing and presentation.1,2 The products of the TAP1 and TAP2 genes form a heterodimeric complex that facilitates transportation of the endogenous peptides into the endoplasmic reticulum, where they associate with MHC class I molecules.1 The proteasomal subunits, LMP2 and LMP7, are believed to conduct in the proteolytic processing of cytosolic and nucleic proteins,2 followed by the translocation of these antigenic peptides by the TAP transporter. HLA-DM (DMA and DMB) has been reported as a critical regulatory molecule in the pathway of class II antigen-restricted antigen processing and presentation to CD41 T lymphocytes.3,4 The DM molecules are involved in the removal of the class II-associated invariant chain peptide and the facilitation of loading with antigen peptides. The TAP1, TAP2, LMP2, DMA, and DMB genes are located between the HLA-DQ and -DP subregions, and
their polymorphisms have been reported.5– 8 The class I and II mediated antigen presentation, which plays an important role in allorecognition after transplantation, may be functionally associated with their genetic polymorphisms. The purpose of this study is to examine whether TAP1, TAP2, LMP2, DMA, and DMB genetic polymorphisms are related to acute rejection after transplantation. We studied a selected population of 50 pairs of donors and recipients who underwent living-related renal transplantation at the Nagoya Daini Red Cross Hospital, the Kakegawa City Hospital, the Yokkaichi City Hospital, and From the Department of Surgery II, Nagoya University School of Medicine and the Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, and the Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan. This study was partly supported by Aichi Kidney Foundation. Address reprint requests to T. Kobayashi, MD, Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466, Japan.
Table 1. Phenotype Frequencies of TAP1, TAP2, LMP2, DMA, and DMB Alleles in Rejection-Free and Rejection (Steroid-Resistant) Groups After Renal Transplantation Recipient
Donor
Rejection (2) (N 5 25)
Rejection (1) (N 5 25)
TAP1*0101 *0201
24 (96%) 9 (36%)
25 (100%) 9 (36%)
24 (96%) 6 (24%)
24 (96%) 7 (28%)
TAP2*0101 *0102 *0103 *0201
17 (68%) 4 (16%) 7 (28%) 11 (44%)b
12 (48%) 6 (24%) 6 (24%) 18 (72%)b
15 (60%) 5 (20%) 12 (48%)a 13 (52%)
19 (76%) 3 (12%) 3 (12%)a 17 (68%)
LMP2-R -H
23 (92%) 12 (48%)
24 (96%) 10 (40%)
21 (84%) 13 (52%)
23 (92%) 13 (52%)
DMA*0101 *0102
24 (96%) 6 (24%)
25 (100%) 6 (24%)
25 (100%) 5 (20%)
24 (96%) 6 (24%)
DMB*0101 *0102 *0103
15 (60%) 13 (52%) 13 (52%)
17 (68%) 13 (52%) 10 (40%)
19 (76%) 11 (44%) 14 (56%)
19 (76%) 12 (48%) 10 (40%)
a b
Rejection (2) (N 5 25)
Rejection (1) (N 5 25)
x2 5 7.714, P 5 .0055, Pc 5 0.022. x2 5 4.023, P 5 .0449, Pc 5 0.1796.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 29–30 (1998)
0041-1345/98/$19.00 PII S0041-1345(97)01170-6 29
30
the Nagoya University Hospital between September 1989 and May 1997. Fifty pairs consisted of a rejection-free group (25 pairs) and a steroid-resistant rejection group (25 pairs). To standardize the effect of HLA matching, all selected pairs possess one HLA haplotype-identical and one DRB1-mismatched combinations. The polymorphisms of the TAP1, TAP2, LMP2, DMA, and DMB genes were analyzed by PCR-RFLP.5– 8 As shown in Table 1, the frequency of TAP2*0103 was significantly increased in donors of the rejection-free group compared to those of the steroid-resistant rejection group (x2 5 7.714, P 5 .0055, Pc 5 0.022). The frequency of TAP2*0201 was considerably higher in recipients of the steroid-resistant rejection group compared to those of the rejection-free group (x2 5 4.023, P 5 .0449, Pc 5 0.1796). There was no significant difference in the allelic frequency of TAP1, LMP2, DMA, or DMB between the rejection-free and steroid-resistant rejection groups. Although it is now difficult to speculate how genetic polymorphisms in the TAP region might influence the allorecognition as a cause of rejection, our results suggest that allelic variation of the TAP2 gene may be associated with the efficiency of donor
KOBAYASHI, YOKOYAMA, HAYASHI ET AL
class I-mediated antigen presentation to recipient T lymphocytes after transplantation. ACKNOWLEDGMENTS We express our appreciation to Hiromi Kamura and Setsuko Kohara, Laboratory for Histocompatibility, Nagoya Daini Red Cross Hospital, and Tomoko Kondo, Department of Surgery II, Nagoya University School of Medicine for excellent technical assistance.
REFERENCES 1. Spies T, Cerundolo V, Colonna M, et al: Nature 355:644, 1992 2. Glynne R, Powis SH, Bech S, et al: Nature 353:357, 1991 3. Morris P, Shaman J, Attaya M, et al: Nature 368:551, 1994 4. Fling SP, Arp B, Pious D: Nature 368:554, 1994 5. Ishihara M, Ohno S, Mlzuki N, et al: Hum Immunol 45:105, 1996 6. Ishihara M, Onho S, Ishida T, et al: Tissue Antigens 49:107, 1997 7. Naruse TK, Kawata H, Ishihara M, et al: Tissue Antigens 47:530, 1997 8. Ishihara M, Naruse T, Ohno S, et al: Hum Immunol 49:144, 1996