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Skrining Antimicrobial Agents untuk In Vitro Perlindungan Radiasi dan Kapasitas Mitigasi,
Termasuk yang Digunakan dalam Rejimen Perawatan Pendukung untuk Penerima Transplantasi
Sumsum Tulang *
1. Michael W. EPPERLY 1,
2. Darcy FRANICOLA1,
3. Donna SHIELDS1,
4. JEAN-CLAUDE RWIGEMA1,
5. BRANDON STONE1,
6. XICHEN ZHANG1,
7. WILLIAM MCBRIDE2,
8. GEORGE GEORGES3,
9. PETER WIPF4 dan
10. Joel S. Greenberger 1
+ Penulis Afiliasi

1.
1Department Radiasi Onkologi, University of Pittsburgh Cancer Institute, Pittsburgh, PA,
USA
2.
2Department Radiasi Onkologi, Roy E. Coats Research Laboratories, David Geffen School
of Medicine, University of California, Los Angeles, CA, USA
3.
3Department Kedokteran, Fred Hutchinson Cancer Research Center, Universitas Washington,
Seattle, WA, Amerika Serikat
4.
4Department Kimia, University of Pittsburgh, Pittsburgh, PA, USA
1. Korespondensi untuk: Joel S. Greenberger, MD, Profesor dan Ketua, Departemen Radiasi
Onkologi, Kanker UPMC Pavilion, POB 2, Lantai 5, Rm. 533, 5150 Pusat Avenue, Pittsburgh,
PA 15232, USA Tel: 412 6473602, Faks: 412 6476029, e-mail: greenbergerjs@upmc.edu
Berikutnya Bagian
Abstrak
Agen antibiotik dan antijamur yang digunakan dalam regimen perawatan suportif untuk
penerima transplantasi sumsum tulang berkontribusi pada efek dosis-memodifikasi signifikan
iradiasi tubuh sebaliknya mematikan total. Untuk menentukan apakah obat yang digunakan
dalam perawatan suportif dan antibiotik lainnya yang umum digunakan seperti fungsi tetrasiklin
sebagai pelindung radiasi atau kerusakan mitigators in vitro, 13 obat yang diuji untuk proteksi
radiasi dan radiasi mitigasi kerusakan 32D 3 sel progenitor hematopoietik dalam cl kurva
survival clonagenic in vitro . Agen antibiotik / anti jamur termasuk silastatin, amikasin,
ceftazidine, vankomisin, tetrasiklin, doksisiklin, siprofloksasin, metronidazol, methacycline,
minocycline, meclocycline, oxytetracycline dan rolitetracycline ditambahkan dalam 1,, 10 atau
100 konsentrasi mikromolar untuk murine interleukin-3-progenitor hematopoietik bergantung sel
line 32D cl 3 sel baik sebelum atau setelah iradiasi 0 sampai 8 Gy. Kontrol diiradiasi 32D cl 3 sel
menunjukkan radiosensitivity sebanding dengan yang baru explanted tikus sel-sel progenitor
hematopoietik sumsum (1,1 0,1 Gy D0, 1,5 0,4). Kontrol positif GS-nitroxide JP4-039
(mitigator radiasi dikenal) diperlakukan 32D cl 3 sel radioresisten (D0 1,2 0,1, 5,8 2,4 (p =
0,009)). Dari 13 obat yang diuji, tetrasiklin ditemukan menjadi mitigator radiasi yang signifikan
(D0 0,9 0,1, 13,9 0,4 (p = 0,0027)). Dengan demikian, radiasi dosis-memodifikasi efek
dari beberapa antibiotik, tapi tidak yang saat ini digunakan dalam perawatan suportif (antibiotik /
antijamur rejimen) untuk pasien transplantasi sumsum, dapat bertindak sebagai mitigators
kerusakan radiasi untuk sel hematopoietik serta mengurangi pertumbuhan dan respon inflamasi
untuk mikroba patogen.
* Antibiotik
* Agen antijamur
* Proteksi radiasi
* Radiasi mitigators
* Transplantasi sumsum tulang

* Mendukung perawatan
Pada hewan percobaan serta protokol klinis transplantasi sumsum tulang, persiapan tuan rumah
untuk infus sel induk hematopoietik donor sering memanfaatkan iradiasi total tubuh atau
kemoterapi sitotoksik (1-5). Dalam model anjing (2-4, 6-12), yang 50/30 LD (dosis yang
memproduksi kematian sumsum tulang pada 50% anjing diiradiasi pada 30 hari setelah iradiasi)
telah mengungkapkan efek dosis yang signifikan memodifikasi (DME) dari antibiotik dan
regimen perawatan suportif antijamur. DME telah ditunjukkan dalam beberapa sistem model
anjing untuk meningkatkan 4-7 Gy (1-3, 13-17). Rejimen perawatan suportif telah dimodifikasi
lebih lanjut dalam beberapa tahun terakhir, dengan ketersediaan yang baru, agen antibiotik dan
antijamur lebih kuat (1-3, 12). Sebuah iradiasi yang sama DME rejimen perawatan suportif telah
dibuktikan dalam anjing (1-4), dan non-manusia model primata yang mencakup transplantasi
sumsum (18).
Antibiotik dan agen antijamur yang digunakan dalam sumsum tulang saat rejimen klinis
transplantasi perawatan suportif telah digabungkan untuk mencegah infeksi oportunistik
difasilitasi oleh leukopenia tulang sumsum-agen beracun, yang meliputi total tubuh iradiasi (1831). Sebuah pertanyaan yang telah muncul selama diskusi dari mekanisme potensi mendukung
perawatan-dimediasi iradiasi DME adalah bahwa satu atau lebih dari agen-agen antimikroba
dapat bertindak sebagai mitigators kerusakan radiasi, di luar tindakan antimikroba mereka.
Mitigators radiasi didefinisikan sebagai agen yang dapat meningkatkan kelangsungan hidup
ketika ditambahkan setelah terpapar radiasi, tapi sebelum munculnya gejala patologis atau
patofisiologi klinis atau efek (32). Mitigators radiasi dikenal digunakan dalam radioterapi klinis
termasuk WR2721 (amifostine) (33), nitroxides (Tempol) (34), dan dalam sistem model
eksperimental, serangkaian baru mitigators molekul kecil kerusakan radiasi (33).
Ada bukti terbaru dari percobaan skrining perpustakaan kimia yang analog beberapa antibiotik
mungkin dikenal memiliki DNA-intercalating kapasitas dan dapat berfungsi untuk merangsang
perbaikan DNA. Data ini telah menyarankan bahwa beberapa agen antimikroba, termasuk yang
digunakan dalam rejimen perawatan suportif, mungkin memiliki sifat kerusakan radiasi
mitigative. Kami menguji efek dari masing-masing dari 13 agen antimikroba, termasuk yang
digunakan dalam sumsum tulang protokol saat ini transplantasi klinis, dalam uji sensitivitas
radiasi memanfaatkan interleukin-3 (IL-3)-bergantung progenitor hematopoietik garis sel murine
32D cl 3 (34 - sebagai garis sel penanda untuk sel induk sumsum tulang manusia) 35.
Sebelumnya Bagian Bagian
Bahan dan Metode
Sel dan kultur sel. Para hematopoietik progenitor sel murine garis 32D cl 3 (34, 35), tergantung
untuk pertumbuhan in vitro pada IL-3 ditumbuhkan dalam media terkandung McCoys
dimodifikasi pada 37 C dalam inkubator kelembaban yang tinggi sesuai dengan metode yang
dipublikasikan (34-35) . Baris ini sel telah terbukti menjadi indikator yang sensitif dari
pelindung radiasi dan sifat-sifat radiasi mitigative obat kandidat baru (33).
Antimikroba agen dan analog. Masing-masing dari 13 obat (Tabel I) telah diuji dalam percobaan
rangkap tiga. Saham solusi dari semua obat yang diperoleh dari Sigma Chemical Co, St Louis,
MO, USA, dibuat dengan melarutkan obat dalam air steril pada konsentrasi 10 mM. Obat diuji

untuk kemampuan mereka untuk memodifikasi radiosensitivity dari 32D baris 3 sel progenitor
hematopoietik murine cl. Antibiotik yang digunakan pada konsentrasi 1, 10, atau 100 pM dengan
menambahkan mereka ke 32D 3 sel cl 1 jam sebelum iradiasi atau segera setelah iradiasi. Sel
diiradiasi dengan dosis berkisar dari 0 sampai 8 Gy, berlapis di methycellulose, dan diinkubasi
pada 37 C selama 7 hari, pada saat koloni yang lebih besar dari 50 sel dihitung (34-35). Data
menunjukkan berarti SEM tiga percobaan terpisah untuk D0 (kemiringan kurva iradiasi akhir
hidup dinyatakan dalam Gy) dan N (bahu pada kurva survival) masing-masing obat. Antibiotik
yang dievaluasi untuk efek mereka pada D0 dan . Beberapa obat bila diberikan pada 100 pM
setelah iradiasi tidak menunjukkan koloni, menunjukkan toksisitas. Radiasi mitigator kontrol
positif JP4-039 ditambahkan pada 10 pM dengan budaya sebelum atau setelah iradiasi,
sebagaimana diterbitkan di tempat lain (36, 37).
Iradiasi kurva kelangsungan hidup. Sel diiradiasi menggunakan Cesium 137 irradiator Gamma
sel, laju dosis 100 cGy / menit selama rentang dosis total 0 sampai 8 Gy. Untuk evaluasi
kapasitas pelindung radiasi, sel-sel diinkubasi selama 24 jam pada setiap konsentrasi antimikroba
sebelum iradiasi. Untuk percobaan mitigasi iradiasi, sel iradiasi disentrifugasi untuk pelet sel
disuspensikan dalam medium dan mengandung 1, 10, atau 100 konsentrasi mikromolar setiap
antimikroba, maka berlapis di metilselulosa 0,8% mengandung medium untuk pengujian kurva
kelangsungan hidup clonogenic. Sel-sel berlapis di 500, 1000, atau 2000 sel per piring dalam
rangkap tiga pada dosis masing-masing menurut metode diterbitkan (34, 35). Semua eksperimen
dilakukan dalam rangkap tiga.
Lihat tabel ini:
* Dalam jendela ini
* Pada jendela baru
Tabel I.
Proteksi radiasi dan / atau kerusakan mitigasi oleh antimikroba perawatan suportif. 32D cl 3 sel
diinkubasi di hadapan pM 1, 10 atau 100 dari antibiotik selama 1 jam sebelum iradiasi atau
ditambahkan ke sel setelah iradiasi 0 sampai 8 Gy. Sel-sel berlapis di methycellulose, diinkubasi
pada 37 C selama tujuh hari pada saat koloni yang lebih besar dari 50 sel dihitung. Data
dianalisis dengan menggunakan linier kuadrat dan single-hit, model multi-target. - Menunjukkan
bahwa tidak ada koloni terdeteksi pada konsentrasi itu. Semua antibiotik diperoleh dari Sigma
Chemical Company, St Louis, MO.
Gambar 1.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 1.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masing-

masing.
Gambar 2.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 2.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 3.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 3.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 4.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 4.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 5.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 5.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang

dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 6.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 6.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 7.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 7.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 8.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 8.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 9.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 9.

Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Pada 7 hari setelah plating, koloni 50 atau lebih sel per koloni diberi skor menggunakan
mikroskop terbalik sesuai dengan metode yang dipublikasikan (34, 35). Data disajikan dengan
menggunakan masing-masing dua program komputer merencanakan linear, kuadrat, dan alfa /
beta model yang sesuai (35).
Sebelumnya Bagian Bagian
Hasil
Radiobiologic efek pada kelangsungan hidup sel 32D 3 cl clonagenic. Kami pertama menguji
pengaruh masing-masing dari 13 agen antibiotik dan antijamur termasuk yang digunakan dalam
rejimen perawatan suportif dalam klinis dan eksperimental (anjing) model transplantasi sumsum
tulang. Hasil pada Tabel I dan Gambar 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 dan 13 menunjukkan
beberapa toksisitas obat pada konsentrasi tinggi (misalnya, doxycycline pada 100 pM setelah
iradiasi ). Para agen antibiotik / antinocardial, minocycline dan rolitetracycline adalah beracun
pada semua dosis ketika ditambahkan setelah iradiasi (Tabel I). Kurva survival penyinaran
dengan 32D cl 3 menunjukkan peningkatan yang signifikan dalam bahu tercermin sebagai ()
dengan penambahan kontrol positif GS-nitroxide, JP4-039 (37) sebelum atau setelah iradiasi
(Tabel I). Tetrasiklin juga mitigator radiasi oleh uji pada 100 pM (Tabel I) (Gambar 8).
Proteksi radiasi dan kerusakan mengurangi sifat analog tetrasiklin. Setiap 6 analog tetrasiklin
dievaluasi oleh skrining perpustakaan kimia yang diuji untuk proteksi radiasi atau properti
kerusakan mitigasi terhadap 32D 3 sel cl pada setiap dari tiga konsentrasi yang dijelaskan dalam
Bahan dan Metode. Agen ini tidak mitigators kerusakan yang signifikan radiasi atau pelindung di
uji 3 32D cl (Tabel I) (Gambar 9, 10, 11, 12 dan 13).
Gambar 10.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 10.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 11.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru

Gambar 11.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 12.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 12.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Gambar 13.
Lihat versi yang lebih besar:
* Pada halaman ini
* Pada jendela baru
Gambar 13.
Masing-masing obat ditambahkan sebelum atau setelah iradiasi untuk 32D sel cl 3 seperti yang
dijelaskan dalam Bahan dan Metode. Sel berlapis dan mencetak gol seperti yang dijelaskan
dalam Bahan dan Metode. Hasil adalah SEM berarti setiap agen pada konsentrasi masingmasing.
Sebelumnya Bagian Bagian
Diskusi
Perkembangan protokol untuk transplantasi sumsum tulang klinis pada pasien dengan leukemia,
limfoma, multiple myeloma, dan non-hematopoietik keganasan sistem telah diperhitungkan
masalah signifikan infeksi oportunistik selama interval antara transplantasi sel induk
hematopoietik donor dan pemulihan perifer jumlah darah putih sel (7-8, 34). Ini interval
leukopenia yang dapat berlangsung 14-30 hari, subjek penerima transplantasi untuk risiko yang
signifikan dari infeksi oportunistik (19, 20). Penggunaan aliran laminar-kamar dan teknik steril
cermat dalam Unit Transplantasi Sumsum telah sangat diminimalkan kejadian dan keparahan
dari infeksi oportunistik (38). Regimen antibiotik dan antijamur yang digunakan dalam
perawatan profilaksis penerima transplantasi sumsum sebelum terapi ablatif (total tubuh iradiasi
atau alkalinating terapi agen) serta setelah infus donor sumsum telah terus-menerus dimodifikasi
dengan ketersediaan lebih baru, kurang toksik antimikroba spektrum luas agen (8-9, 12).

Penerima transplantasi sumsum tulang disusun dengan menggunakan teknik fraksi tunggal atau
total difraksinasi tubuh iradiasi pada dosis radiasi yang menghasilkan sindrom hematopoietik.
Sindrom hematopoietik adalah dengan salah satu definisi yang dapat dikoreksi dengan
penggantian sel-sel induk hematopoietik (32). Gastrointestinal, paru, atau non-hematopoietik
organ reversibel rusak oleh radiasi tidak diselamatkan oleh transplantasi sumsum tulang (33).
Dosis iradiasi total tubuh, skema fraksinasi, dan upaya untuk melindungi non-hematopoietik
jaringan seperti paru-paru, menggunakan blok transmisi paru telah menetapkan pedoman untuk
dosis radiasi yang tepat dan preparatif rejimen (26).
Hal ini juga diasumsikan bahwa obat ini bekerja sekunder untuk mengurangi respon sitokin
inflamasi terhadap infeksi. Rejimen perawatan suportif mungkin juga memiliki utilitas dalam
pengelolaan para korban kecelakaan iradiasi yang tidak mungkin menjadi kandidat untuk
transplantasi sumsum (32).
Dalam studi ini, kami berusaha untuk menentukan apakah antibiotik tetrasiklin umum serta satu
atau lebih agen yang digunakan dalam rejimen perawatan modern yang mendukung juga
bertindak sebagai mitigators kerusakan radiasi. Untuk menentukan apakah molekul kecil
termasuk antibiotik atau antijamur agen yang bertindak sebagai mitigators kerusakan radiasi
pada tingkat selular dasar, suatu dalam sistem in vitro assay hidup clonagenic digunakan (39).
Tes cepat untuk apoptosis diinduksi radiasi langsung, atau sel mati setelah pembelahan sel
pertama nilai serta (36). Kurva kelangsungan hidup clonogenic langkah-langkah kematian sel
dalam 7 doubling pertama sel setelah iradiasi, dan memungkinkan deteksi peristiwa mematikan
yang dapat ditunda masa lalu pembelahan sel pertama (36). Hasil penelitian menunjukkan bahwa
tetrasiklin, seperti obat kontrol positif JP4-039 (37), adalah seorang mitigator radiasi secara in
vitro. Studi lain menggunakan skrining siRNA mRNA target doksisiklin diidentifikasi sebagai
radioprotector potensial, tetapi obat itu tidak efektif dalam studi itu, seperti dalam studi hadir
dalam tes kurva kelangsungan hidup clonagenic menggunakan 32D cl 3 sel, juga tidak efektif
dalam vivo (39) .
Penelitian ini mendukung upaya untuk merancang generasi masa depan antibiotik dan agen
antijamur dengan tujuan juga menggunakan mereka sebagai mitigators kerusakan radiasi. Agen
antibakteri / antijamur dapat dimodifikasi untuk memiliki jaringan radiasi kapasitas mitigasi
normal untuk membantu pemulihan dari penerima transplantasi total tubuh iradiasi atau korban
radiasi teroris. Kekhawatiran untuk aplikasi klinis akan mencakup konfirmasi bahwa agen tidak
mengubah sel tumor membunuh efek dari total tubuh iradiasi. Skrining antimikroba baru serta
yang digunakan dalam klinis rejimen perawatan suportif untuk kapasitas mitigasi kerusakan
radiasi harus nilai dalam pengembangan pengobatan bagi korban kecelakaan radiasi dan
terorisme radiasi.
Sebelumnya Bagian Bagian
Catatan kaki
*
* Didukung oleh: NIH / NIAD U19AI068021, U19AI067769, U19AI067770,
U19A1067769.
*

o Diterima 20 Oktober 2009.


o Revisi diterima 16 Desember 2009.
o Diterima 18 Desember 2009.
* Copyright 2010 Institut Internasional Penelitian Antikanker (Dr John G. Delinassios), All
rights reserved
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Articles by Espinoza, J. L.

Stem Cell Transplantation

NKG2D gene polymorphism has a significant impact on


transplant outcomes after HLA-fully-matched unrelated bone
marrow transplantation for standard risk hematologic
malignancies
J. Luis Espinoza1, Akiyoshi Takami1, Makoto Onizuka2, Hiroshi Sao3, Hideki
Akiyama4, Koichi Miyamura5, Shinichiro Okamoto6, Masami Inoue7,
Yoshinobu Kanda8, Shigeki Ohtake1, Takahiro Fukuda9, Yasuo Morishima10,
Yoshihisa Kodera11, Shinji Nakao1 for the Japan Marrow Donor Program
1

Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa


Department of Hematology and Oncology, Tokai University School of Medicine, Isehara
3
Department of Hematology, Meitetsu Hospital, Nagoya
4
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo
5
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya
6
Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo
7
Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child
Health, Osaka
8
Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama
9
Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo
10
Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya
11
Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagoya, Japan
2

Correspondence: Akiyoshi Takami, M.D., Ph.D., Department of Hematology & Oncology, Kanazawa University
Hospital, 13-1 Takaramachi, Kanazawa, 920-8641, Japan. E-mail:takami@med3.m.kanazawa-u.ac.jp

ABSTRACT
TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

Background: NKG2D, an activating and co-stimulatory receptor expressed on natural


killer cells and T cells, plays pivotal roles in immunity to microbial infections as well
as in cancer immunosurveillance. This study examined the impact of donor and
recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients
undergoing allogeneic T-cell-replete myeloablative bone marrow transplantation
using an HLA-matched unrelated donor.

Design and Methods: The NKG2D polymorphism was retrospectively analyzed in a total 145
recipients with hematologic malignancies and their unrelated donors. The patients underwent
transplantation following myeloablative conditioning; the recipients and donors were matched
through the Japan Marrow Donor Program.
Results: In patients with standard-risk disease, the donor NKG2D-HNK1 haplotype, a haplotype
expected to induce greater natural killer cell activity, was associated with significantly improved
overall survival (adjusted hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) as
well as transplant related mortality (adjusted hazard ratio, 0.42; 95% confidence interval, 0.21 to
0.86; p=0.02), but had no impact on disease relapse or the development of grade IIIV acute
graft-versus-host disease or chronic graft-versus-host disease. The NKG2D polymorphism did not
significantly influence the transplant outcomes in patients with high-risk disease.
Conclusions: These data suggest an association between the donor HNK1 haplotype and better
clinical outcome among recipients, with standard-risk disease, of bone marrow transplants
from HLA-matched unrelated donors.
Key words: NKG2D, HNK1, LNK1, unrelated donor, bone marrow transplantation, single
nucleotide polymorphism.

Introduction
TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

Hematopoietic stem cell transplantation (SCT) is a potentially curative treatment


for a range of hematologic malignancies. Although the use of an HLA-matched
unrelated donor is well accepted when an HLA-identical sibling donor is unavailable,
the risk of transplantation- related complications may be increased.1 Despite
improvements in clinical and supportive care, transplant- related life-threatening
complications, including graft-versus-host disease (GVHD), infections and disease
relapse, remain an enormous obstacle to overcome.2 Although HLA matching is the
major genetic determinant of clinical outcome after allogeneic SCT, recent evidence
suggests that non-HLA immune-associated genes are also implicated.3 Previous
investigations have revealed that several single nucleotide polymorphisms (SNP)
which affect individual immune response to infections and inflammatory reactions
are associated with the risk of GVHD and transplant outcomes.415

NKG2D is an activating and co-stimulatory receptor belonging to the C-type lectin-like family of
transmembrane proteins and is expressed as a homodimer on natural killer (NK) cells, CD8+ +
T cells, + T cells and activated macrophages.1618 The ligands for NKG2D, such as MHC class Ichain related proteins (MICA and MICB), UL16 binding proteins are usually absent or expressed
at very low levels in normal cells but are up-regulated by cellular stress including heat shock and
microbial infections and are frequently expressed in epithelial tumor cells.19 Ligand engagement
of NKG2D triggers cell-mediated cytotoxicity and co-stimulates cytokine production through a
DAP10-phosphoinositol 3-kinase dependent pathway and plays an important role in the
elimination of tumors and infected cells.1618,20
Recently, SNP were identified between LNK1 and HNK1 haplotypes of the NKG2D gene.21 In
Japanese individuals, the HNK1 haplotype is associated with greater activity of NK cells in the
peripheral blood21,22 and a lower prevalence of cancers originating from epithelial cells.21,23,24 The
present study investigates the impact of donor and recipient polymorphisms in the NKG2D gene
on the clinical outcomes of patients undergoing allogeneic myeloablative bone marrow
transplantation using an HLA allele-matched unrelated donor.

Design and Methods


TOP
ABSTRACT
Introduction
Design and Methods
Results

Discussion
References

Patients
NKG2D genotyping was performed on a total 145 recipients with hematologic
malignancies and their unrelated donors who were part of the Japan Marrow Donor
Program (JMDP). The recipients underwent transplantation, following myeloablative
conditioning, with T-cell-replete marrow from an HLA-A, -B, -C, -DRB1 allelematched donor between November 1995 and March 2000. HLA genotypes of the
HLA-A, -B, -C, and -DRB1 alleles of the patients and donors were determined by the
Luminex microbead method described previously. (Luminex 100 System; Luminex,
Austin, TX, USA).25,26 No patient had a history of prior transplantation. The final
clinical survey of these patients was completed by November 1, 2007. Diagnoses
were acute myeloid leukemia (n=49; 34%), acute lymphoblastic leukemia (n=37;
26%), chronic myeloid leukemia (n=41; 28%), myelodysplastic syndrome (n=11;
8%) and malignant lymphoma (n=7; 5%), (Table 1). The recipients were defined as
having standard risk disease if they had acute myeloid or lymphoblastic leukemia in
first complete remission, malignant lymphoma in complete remission, chronic
myeloid leukemia in any chronic phase or myelodysplastic syndrome. All other
patients were designated as having high-risk disease. Myeloid malignancies included
acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome,
whereas lymphoid malignancies included acute lymphoblastic leukemia and
malignant lymphomas. Cyclosporine or tacrolimus- based regimens were used in all
patients for GVHD prophylaxis whereas anti-T-cell therapy, such as anti-thymocyte
globulin and ex vivo T-cell depletion, was not. All patients and donors gave their
written informed consent to molecular studies, according to the declaration of
Helsinki, at the time of transplantation. The project was approved by the
Institutional Review Board of Kanazawa University Graduate School of Medicine and
the JMDP.

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Table 1. Characteristics of the donors and recipients.

NKG2D genotyping
NKG2D was genotyped using the TaqMan-Allelic discrimination method27 with a 9700-HT real
time polymerase chain reaction (PCR) system (Applied Biosystems, Foster City, CA, USA) and

results were analyzed using allelic discrimination software (Applied Biosystems). The
genotyping assay was conducted in 96-well PCR plates. The amplification reaction contained
template DNA, TaqMan universal master mix and a specific probe (product No. C_9345347_10;
Applied Biosystems) for rs1049174, a single locus featuring a G-C substitution to distinguish
between the HNK1 (G) and LNK1 (C) haplotypes of the NKG2D gene.21,23,24
Data management and statistical analysis
Data were collected by the JMDP using a standardized report form. Follow-up reports were
submitted at 100 days, 1 year and annually after transplantation. Pre-transplant
cytomegalovirus serostatus was routinely tested only in patients but not in their donors.
Engraftment was confirmed by an absolute neutrophil count of more than 0.5x109/L for at least 3
consecutive days. Acute and chronic GVHD were diagnosed and graded using established
criteria.28,29 Overall survival was defined as the number of days from transplantation to death
from any cause. Disease relapse was defined as the number of days from transplantation to
disease relapse. Transplant-related mortality was defined as death without relapse. Any patients
who were alive at the last-follow-up date were censored. When collecting data, only the main
cause of death was recorded if two or more causes were combined. Data on etiological agents of
infections, postmortem changes and supportive care (including prophylaxis of infections and
therapy of GVHD, which were given on an institutional basis), were not available for this cohort
of patients. The analysis was performed using Excel 2007 (Microsoft Corp, Redmond, WA,
USA), OriginPro version 8.0J (Lightstone Inc, Tokyo, Japan), and R (The R Foundation for
Statistical Computing, Perugia, Italy).30 The probability of overall survival was calculated using
the Kaplan-Meier method and compared using the log-rank test. The probabilities of transplantrelated mortality, disease relapse, acute GVHD, chronic GVHD, and each cause of death were
compared using the Grey test31 and analyzed using cumulative incidence analysis,30 considering
relapse, death without disease relapse, death without acute GVHD, death without chronic GVHD,
and death without each cause as respective competing risks. The analysis was stratified for
patients with standard-risk disease and high-risk disease to take into account the already
recognized prognostic differences. The variables considered were recipient age at time of
transplantation, sex, recipient cytomegalovirus serostatus before transplantation, disease
characteristics (disease type and disease lineage), donor characteristics (age, sex, sex
compatibility, and ABO compatibility), transplant characteristics (total body irradiationcontaining regimen, tacrolimus versus cyclosporine, and total nucleated cell count harvested per
recipient weight). The median was used as the cut-off point for continuous variables. The 2 test
and Mann-Whitney test were used to compare results of two groups. The Hardy-Weinberg
equilibrium for the NKG2D gene polymorphism was tested using the Haploview program.32
Multivariate Cox models were used to evaluate the hazard ratio associated with the NKG2D
polymorphism. Covariates found to be statistically significant in univariate analyses (p 0.10)
were included in the models. For both the univariate and multivariate analyses, p values were
two-sided and outcomes were considered to be statistically significant with p 0.05.

Results
TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

Frequencies of NKG2D haplotype


The NKG2D gene polymorphism was analyzed in 145 pairs of unrelated donorsrecipients of bone marrow following myeloablative conditioning (Table 1). The
haplotype frequencies of LNK1/LNK1, HNK1/LNK1 and HNK1/HNK1 were 43%, 42%
and 15%, respectively in donors and 35%, 45% and 20%, respectively in recipients.
These frequencies were similar to those reported in previous studies in Japanese
populations21,24 and were in accordance with the Hardy-Weinberg equilibrium
(p=0.80).

Transplant outcomes according to NKG2D haplotype


With a median follow-up of 115 months among survivors (range, 74 to 140 months), 30
recipients (21%) had relapsed or progressed and 62 (47%) had died. Three patients (2%) died
before engraftment. The analysis of the influence of the NKG2D genotype on clinical outcomes
after transplantation was stratified according to whether the recipients had standard-risk disease
or high-risk disease to account for the already recognized prognostic difference. The overall
survival at 5 years in patients with standard-risk disease was 63% while that of patients with
high-risk disease was 44% (p=0.06). The 5-year cumulative incidences of trasplant-related
mortality were 32% and 27%, respectively (p=0.33) and those of disease relapse were 10% and
31%, respectively (p=0.0006).
The transplant outcomes according to NKG2D genotype are summarized in Table 2. Patients
with standard-risk disease receiving transplants from donors with the HNK1 haplotype had a
significantly better 5-year overall survival (73% vs. 49%, p=0.01; Figure 1A) and lower
transplant-related mortality rate (22% vs. 45%, p=0.02; Figure 1B) than those receiving
transplants from donors without the HNK1 haplotype. No difference was noted in disease
relapse in relation to the donors polymorphism (9% vs. 11%, p=0.81; Figure 1C) or in the

development of grades II to IV acute GVHD (28% vs. 41%, p=0.25) or chronic GVHD (37% vs.
41%, p=0.83). When patients with acute myeloid leukemia or myelodysplastic syndrome were
separately analyzed, there was still no difference in disease relapse in relation to NKG2D
polymorphisms (data not shown). In patients with high-risk disease, the donor HNK1 haplotype
had no significant effects on transplant outcomes (Table 2).

View this
table:
[in this
window]
[in a new
window]
[Download
PPT slide]

Table 2. Univariate analysis of the association of NKG2D


polymorphisms with clinical outcomes after transplantation.

Figure 1. Kaplan-Meier analysis of (A) overall survival, (B)


cumulative incidence of transplant-related mortality and (C)
disease relapse after transplantation according to the donor
NKG2D polymorphism in patients with standard-risk disease.
View larger Patients with donors with the HNK1 haplotype had better overall
version
survival and lower transplant-related mortality. Donor
(10K):
haplotype had no significant impact on disease relapse.
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Multivariate analysis
Any factors found to be significant in univariate analyses were included in the multivariate
analysis. When patients with standard-risk disease were analyzed, the HNK1 haplotype in donors
remained statistically significant in multivariate analyses for both overall survival and
transplant-related mortality (Table 3). The presence of the HNK1 haplotype in the donor
resulted in better overall survival (hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85;
p=0.01) and transplant-related mortality (hazard ratio, 0.42; 95% confidence interval, 0.21 to
0.86; p=0.02). The donor and recipient HNK1 haplotype did not significantly influence the
transplant outcomes in patients with high-risk disease.

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Table 3. Multivariate analysis of the association of NKG2D


polymorphisms with clinical outcomes after transplantation.

Main causes of death


The main causes of death according to the HNK1 haplotype of the donors and recipients are
illustrated in Figure 2A for patients with standard-risk disease, and in Figure 2B for those with
high-risk disease. In patients with standard-risk disease receiving transplants from HNK1negative donors, the most frequent cause of death was acute GVHD, followed by interstitial
pneumonia. Transplants from HNK1-positive donors resulted in a statistically significantly
reduced incidence of death attributed to acute GVHD (Figure 3A; p=0.006) as well as a trend
toward a lower incidence of death attributed to interstitial pneumonia (Figure 3B; p=0.09). Other
causes of death did not differ according to the HNK1 haplotype.

Figure 2. Main causes of death after transplantation


according to the NKG2D polymorphism in patients with
(A) standard-risk disease (B) high-risk disease.
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Discussion

Figure 3. Cumulative incidence of deaths due to (A) acute


GVHD and (B) interstitial pneumonia after transplantation
in patients with standard-risk disease. The HNK1 haplotype
in donors was associated with a significantly lower
incidence of deaths due to acute GVHD (p=0.006) as well
as a trend toward a lower incidence of deaths due to
interstitial pneumonia (p=0.09).

TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

The current study showed an association between the NKG2D-HNK1 haplotype in


unrelated donors of HLA-matched myeloablative bone marrow transplants
(haplotype frequency, 61%) and a significantly reduced transplant-related
mortality and better overall survival for their recipients with standard-risk disease.
The polymorphism of the donor NKG2D gene did not influence disease relapse or the
development of grades II to IV acute GVHD or chronic GVHD in the patients. One
possible explanation for the absence of the beneficial effects of the HNK1 haplotype
in patients with high-risk disease may be that the number of cases in the study was
insufficient for a meaningful assessment of the effect. Alternatively, disease
progression may precede the emergence of the potential advantageous effects of
the HNK1 donor haplotype that could protect the recipient from severe transplantrelated complications. There was a larger difference in disease relapse between
patients with standard-risk disease and those with high-risk disease: 10% and 31%
at 3 years after transplantation, respectively.

NKG2D plays important roles in immunity to microbial infections and is especially prominent in
controlling viral and bacterial infections.16 Therefore, the reduced transplant-related mortality in
patients with standard-risk disease receiving grafts from donors with the HNK1 haplotype in this
study might be a consequence of increased resistance to infections in the recipients. However, the
hypothesis is too speculative because of the unavailability of data on causes of infections in this
cohort. Further studies will be needed to clarify whether the HNK1 haplotype in donors can
effectively protect patients against infections.
Several studies have shown that NK cell activity has an important role in the outcomes of
patients undergoing allogeneic transplantation.33,34 Alloreactive NK cells reduced the risk of
relapse of acute myeloid leukemia without increasing the incidence of GVHD, resulting in a
marked improvement of event-free survival in a series of haploidentical transplant recipients.35,36
In HLA-identical sibling transplants, the absence of HLA-C and HLA-B ligand for donorinhibitory killer immunoglobulin-like receptors (KIR) provided benefits in terms of survival and
relapse of patients with acute myeloid leukemia and myelodysplastic syndrome in recipients of Tcell-depleted SCT.37 On the other hand, the JMDP found that KIR ligand mismatch was
unfavorably correlated with relapse of leukemia and survival in patients undergoing T-cell-replete
unrelated bone marrow transplants.38 All patients in the present study received grafts from an

HLA-A, -B, and -C allele-matched donor, implying KIR ligand match between each patient and
donor. It is an open question whether the NKG2D polymorphism could affect the outcomes of
patients undergoing transplantation with KIR-mismatched grafts.
In this study, major and minor ABO incompatibilities between the donor and recipient tended to
be associated with poorer transplant outcomes, regardless of the risk category of the disease.
These findings are compatible with those of a previous study by the JMDP,39 although the impact
of ABO incompatibilities on SCT outcomes is controversial.
This study also identified age as a significant predictive factor for transplant-related mortality in
the patients with standard-risk disease. This is consistent with the results of a previous study40
showing that age over 35 years increased the risk of transplant-related mortality after allogeneic
myeloablative SCT in high-risk patients.
A possible limitation of this study is the fact that no direct evidence is yet available regarding the
ability of NKG2D polymorphisms to protect against microbial infections. The association
observed between the NKG2D haplotype and transplant outcome might be due to another
genetic polymorphism in linkage disequilibrium responsible for a better transplant outcome.
One candidate gene is NKG2F (KLRC4), which is located in the NK complex region adjacent to
the NKG2D gene, because an intrinsic SNP (rs2617171) in the gene has been reported to be in
complete linkage with the NKG2D genotype.24 Alternatively, polymorphisms may not be directly
associated with controlling infection, but rather may be associated with other factors, such as
sensitivity to treatment against GVHD or protection against organ toxicities related to
transplants, which also influence the transplant outcome. These hypotheses have yet to be
verified give the insufficient evidence.
Polymorphisms in genes encoding for nucleotide-binding oligomerization domain 2
(NOD2)/caspase recruitment domain 15 (CARD15),9 heme oxygenase-1 (HO-1) promoter,6 the
Toll-like receptor 4,4 CC chemokine ligand (CCL) 5 promoter,32 transforming growth factor
(TGF) 1,11 interleukin (IL) 12, tumor necrosis factor (TNF) ,15 IL-23,5 mannose-binding lectin
(MBL),10 Fc receptor IIa (Fc RIIa), myeloperoxidase (MPO), Fc RIIIb, IL-1Ra, IL-10,12 Fc
receptor-like 3 (FCRL3), peptidylarginine deiminase citullinating enzymes 4 (PADI4)13 and
methylenetetrahydrofolate reductase (MTHFR)14 have been shown to influence the outcome after
allogeneic SCT. Most of them are associated with the development of GVHD. Only the
NOD2/CARD15 and HO-1 promoter polymorphisms have a significant impact on overall
survival after SCT. Furthermore, the impact of the HO-1 promoter polymorphisms depends on
donor cells but not on recipient cells, as observed with the NKG2D polymorphism which, in the
donor, was shown to be significantly associated with overall survival in the present study. This
may prompt the determination of the donor NKG2D polymorphism prior to SCT in order to
choose the best donor, expected to minimize transplant-related mortality after SCT, when
multiple donors for a patient are available. Otherwise, prior information on the donor NKG2D

polymorphism may be helpful in selecting risk-specific appropriate precautions following


transplantation.
In conclusion, the present data suggest that the NKG2D polymorphism, in addition to HLA
disparity between recipients and donors, affects prognosis after a bone marrow transplant from
an unrelated donor. However, care should be made in drawing conclusions because the number of
patients in the present study was small. The finding of a gene polymorphism may not be
equivalent to differences in gene expression, which may be influenced by multiple factors
because the NKG2D receptor is found on many tissues and cells.41 Experimental evidence is
required to substantiate the effect of the NKG2D polymorphism on immune function. We next
plan to conduct a prospective study to confirm these results and to extend this investigation to
other transplantation settings, such as related donor SCT, reduced-intensity SCT, HLAmismatched SCT and SCT for patients with non-hematologic malignancies.

Acknowledgments
we are indebted to Drs. Hiroko Oshima, Masanobu Oshima and Atsushi Hirao, Mrs.
Shinichi Ohmae and Katsuya Nakata, and Ms. Kaori Matsuura at Kanazawa
University, and Drs. Keitaro Matsuo and Takakazu Kawase at the Aichi Cancer Center
Research Institute for their technical assistance. We thank all of the JMDP
transplant teams who contributed patients and donors to this study.

Footnotes
Authorship and Disclosures

JLE and AT designed and performed the research, and contributed to the same aspects of the
work; AT, JLE and SN wrote the paper; AT, YKa, and SOh performed the statistical analyses;
MO, HS, HA, KM, SOk, MI, TF, YM, and YKo contributed to data collection.
The authors reported no potential conflicts of interest.

Funding: this study was supported by grants from the Ministry of Health, Labor and Welfare, and
the Ministry of Education, Culture, Sports and Technology, and funds from the Mitani Research
and Development Assistance Organization (Kanazawa, Japan) and by the Japan Leukemia
Research Fund (Tokyo, Japan).
Received for publication March 5, 2009. Revision received April 13, 2009. Accepted for
publication April 29, 2009.

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