Portada Simposios - Supplements - Haematologica
Portada Simposios - Supplements - Haematologica Portada Simposios - Supplements - Haematologica
XLII Reunión Nacional de la AEHH y XVI Congreso de la SETH. Programa educacional 59 12. Langrehr JM, Murase N, Markus PM et al. Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat. J Clin Invest 1992; 90: 679-683. 13. Hattori K, Hirano T, Miyajima H et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies. Blood 1998; 91: 4051-4055. 14. Mori T, Nishimura T, Ikeda Y et al. Involvement of Fas-mediated apoptosis in the hematopoietic progenitor cells of graft-versus-host reaction-associated myelosuppression. Blood 1998; 92: 101-107. 15. Rus V, Svetic A, Nguyen P et al. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8 + T cells. J Immunol 1995; 155: 2396-2406. 16. Nikolic B, Lee S, Bronson RT et al. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest 2000; 105: 1289-1298. 17. Yang YG, Dey BR, Sergio JJ et al. Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 1998; 102: 2126-2135. 18. Krenger W, Falzarano G, Delmonte J, Jr. et al. Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood 1996; 88: 1113-1121. 19. Krenger W, Snyder KM, Byon JC et al. Polarized type 2 alloreactive CD4 + and CD8 + donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol 1995; 155: 585-593. 20. Fowler DH, Kurasawa K, Smith R et al. Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood 1994; 84: 3540-3549. 21. Yabe M, Yabe H, Hattori K et al. Role of interleukin-12 in the development of acute graft-versus-host disease in bone marrow transplant patients. Bone Marrow Transplant 1999; 24: 29-34. 22. Sykes M, Pearson DA, Taylor PA et al. Dose and timing of interleukin (IL)-12 and timing and type of total-body irradiation: effects on graft-vs.-host disease inhibition and toxicity of exogenous IL-12 in murine bone marrow transplant recipients. Biol Blood Marrow Transplant 1999; 5: 277-284. 23. Hill GR, Cooke KR, Teshima T et al. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation. J Clin Invest 1998; 102: 115-123. 24. Teshima T, Hill GR, Pan L et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest 1999; 104: 317-325. 25. Saito K, Sakurai J, Ohata J et al. Involvement of CD40 ligand-CD40 and CTLA4-B7 pathways in murine acute graft-versus-host disease induced by allogeneic T cells lacking CD28. J Immunol 1998; 160: 4225-4231. 26. Gribben JG, Guinan EC, Boussiotis VA et al. Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool. Blood 1996; 87: 4887-4893. 27. Blazar BR, Taylor PA, Linsley PS et al. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 1994; 83: 3815-3825. 28. Przepiorka D, Kernan NA, Ippoliti C et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 2000; 95: 83-89. 29. Williamson E, Garside P, Bradley JA et al. Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol 1997; 159: 1208-1215. 30. Hill GR, Teshima T, Gerbitz A et al. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia. J Clin Invest 1999; 104: 459-467. 31. Krijanovski OI, Hill GR, Cooke KR et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999; 94: 825-831. 32. Panoskaltsis-Mortari A, Lacey DL, Vallera DA et al. Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood 1998; 92: 3960-3967. 33. Locatelli F, Rondelli D,Burgio GR. Tolerance and hematopoietic stem cell transplantation 50 years after Burnet’s theory. Exp Hematol 2000; 28: 479-489. 34. Guinan EC, Boussiotis VA, Neuberg D et al. Transplantation of anergic histoincompatible bone marrow allografts [see comments]. N Engl J Med 1999; 340: 1704-1714. 35. Sakurai J, Ohata J, Saito K et al. Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory CD8 + T cells. J Immunol 2000; 164: 664-669. 36. Durie FH, Aruffo A, Ledbetter J et al. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest 1994; 94: 1333-1338.
ADVANCES IN APPLICATION OF THE HLA SYSTEM IN HAEMOPOIETIC CELL TRANSPLANTATION A. MADRIGAL, MD, PHD, MRCPATH, FRCP The Anthony Nolan Research Institute, The Royal Free Hospital. Selection for voluntary unrelated donors (VUD) for unrelated bone marrow transplantation (BMT) generally relies on matching for HLA-A, B and DR antigens. Initial studies have shown that recipients of transplants from unrelated donors matched for these HLA antigens have a lower risk of acute GVHD that recipients of marrow from mismatched VUD, but this risk was still much higher than that observed for HLA-identical sibling transplants (Madrigal et al. 1997). Improvement of overall survival was not apparent in HLA-A, B, DR matched unrelated recipients when compared with mismatched related recipients. Thus the effect of HLA matching on survival after unrelated transplantation has been controversial. It is now becoming clear that multiple factors could be associated with these results such as a) the presence of unidentified HLA-A, B and DR disparities due to the low resolution HLA typing techniques used, b) incompatibility for other HLA loci such as HLA-C, DQ, and DP, c) mismatched minor transplantation antigens and d) non-HLA factors. At present, the typing of most unrelated individuals for class I antigens is still achieved with serology. In addition to serological typing, cellular assays, e.g. the MLC reaction (Dupont et al, 1980) have served as secondary definition of class II molecular diversity. During the past 10 years, over 800 new HLA alleles have been recognised by DNA sequencing analysis and many more probably remain to be identified. With the discovery of these new alleles, it became obvious that serological specificities comprise multiple undetected molecular subtypes. For example, there are currently over 100 recognised HLA-A alleles and of these only a fraction can be typed by routine serology. Improvements in DNA-based methods for the detection of the many HLA alleles have provided the opportunity to investigate the relationship between HLA disparity and trasplant complications (Fleischhaurer et al, 1990; Scott et al, 1998). Tissue typing techniques are limited by the extensive polymorphism of HLA genes. A pairwise comparison of the nucleotide sequences of known HLA alleles indicates that genetic recombination has played a key role in the generation of HLA diversity. Inter-allelic conversion or double recombination is the principal mechanism wich generates HLA diversity. For HLA class I alleles the highest frequencies of substitutions occur within exons 2 and 3, which encode the a1 and a2 domains of the HLA molecules and for practical purposes 97 % of HLA class I alleles can be identified by sequence based analysis of exons 2 and 3. In contrast, for HLA class II alleles, the highest frequency of substitutions occurs mainly in exon 2 of the b chain. Molecular typing methods include: restriction fragment length polymorphism analysis (RFLP), sequence-specific primer amplification (SSP), hybridisation with sequence-specific oligonucleotide probes (SSO). Heteroduplex analysis, single strand conformation polymorphism (SSCP), and direct nucleotide sequencing. The techniques most commonly used are SSP and SSO (Jordan et al, 1995). SSP utilises group and/or allele specific sequences for PCR primer design and SSO typing is based on the identification of allele specific sequences using oligoprobes which either in unique or in certain combinations allow allele identification. Heteroduplex analysis and SSCP allow comparison of the conformation of DNA molecules, and these are used as supplementary methods by tissue typing laboratories for allelic subtyping. Direct sequencing in principle allows the most accurate typing of HLA alleles. We have recently described a novel high resolution DNA based typing technique which offers a level of resolution similar to direct sequencing techniques, without the problem of heterozygous ambiguities (Arguello et al, 1998). The method, now known as reference Strand mediated Conformation Analysis (RSCA), analyses the conformation of HLA DNA duplexes. Chimeric duplexes are formed between a locus-specific fluorescently labelled reference strand (FLR) and the locus specific alleles from the sample to be typed. The duplexes formed are resolved by polyacrylamide gel electrophoresis (PAGE) in an automated DNA sequencing instrument with a laser based fluorimetric detection system (Arguello et al, 1998). Only duplexes formed with labelled reference sense strands are observed, i.e. two bands for a homozygous sample (labelled reference homoduplex
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XLII Reunión Nacional de la AEHH y XVI Congreso de la SETH. Programa educacional<br />
59<br />
12. Langrehr JM, Murase N, Markus PM et al. Nitric oxide production in<br />
host-versus-graft and graft-versus-host reactions in the rat. J Clin Invest<br />
1992; 90: 679-683.<br />
13. Hattori K, Hirano T, Miyajima H et al. Differential effects of anti-Fas ligand<br />
and anti-tumor necrosis factor alpha antibodies on acute<br />
graft-versus-host disease pathologies. Blood 1998; 91: 4051-4055.<br />
14. Mori T, Nishimura T, Ikeda Y et al. Involvement of Fas-mediated apoptosis<br />
in the hematopoietic progenitor cells of graft-versus-host reaction-associated<br />
myelosuppression. Blood 1998; 92: 101-107.<br />
15. Rus V, Svetic A, Nguyen P et al. Kinetics of Th1 and Th2 cytokine production<br />
during the early course of acute and chronic murine graft-versus-host<br />
disease. Regulatory role of donor CD8 + T cells. J Immunol<br />
1995; 155: 2396-2406.<br />
16. Nikolic B, Lee S, Bronson RT et al. Th1 and Th2 mediate acute<br />
graft-versus-host disease, each with distinct end-organ targets. J Clin Invest<br />
2000; 105: 1289-1298.<br />
17. Yang YG, Dey BR, Sergio JJ et al. Donor-derived interferon gamma is required<br />
for inhibition of acute graft-versus-host disease by interleukin<br />
12. J Clin Invest 1998; 102: 2126-2135.<br />
18. Krenger W, Falzarano G, Delmonte J, Jr. et al. Interferon-gamma suppresses<br />
T-cell proliferation to mitogen via the nitric oxide pathway during<br />
experimental acute graft-versus-host disease. Blood 1996; 88:<br />
1113-1121.<br />
19. Krenger W, Snyder KM, Byon JC et al. Polarized type 2 alloreactive<br />
CD4 + and CD8 + donor T cells fail to induce experimental acute<br />
graft-versus-host disease. J Immunol 1995; 155: 585-593.<br />
20. Fowler DH, Kurasawa K, Smith R et al. Donor CD4-enriched cells of<br />
Th2 cytokine phenotype regulate graft-versus-host disease without impairing<br />
allogeneic engraftment in sublethally irradiated mice. Blood<br />
1994; 84: 3540-3549.<br />
21. Yabe M, Yabe H, Hattori K et al. Role of interleukin-12 in the development<br />
of acute graft-versus-host disease in bone marrow transplant patients.<br />
Bone Marrow Transplant 1999; 24: 29-34.<br />
22. Sykes M, Pearson DA, Taylor PA et al. Dose and timing of interleukin<br />
(IL)-12 and timing and type of total-body irradiation: effects on<br />
graft-vs.-host disease inhibition and toxicity of exogenous IL-12 in murine<br />
bone marrow transplant recipients. Biol Blood Marrow Transplant<br />
1999; 5: 277-284.<br />
23. Hill GR, Cooke KR, Teshima T et al. Interleukin-11 promotes T cell polarization<br />
and prevents acute graft-versus-host disease after allogeneic<br />
bone marrow transplantation. J Clin Invest 1998; 102: 115-123.<br />
24. Teshima T, Hill GR, Pan L et al. IL-11 separates graft-versus-leukemia effects<br />
from graft-versus-host disease after bone marrow transplantation.<br />
J Clin Invest 1999; 104: 317-325.<br />
25. Saito K, Sakurai J, Ohata J et al. Involvement of CD40 ligand-CD40 and<br />
CTLA4-B7 pathways in murine acute graft-versus-host disease induced<br />
by allogeneic T cells lacking CD28. J Immunol 1998; 160: 4225-4231.<br />
26. Gribben JG, Guinan EC, Boussiotis VA et al. Complete blockade of B7<br />
family-mediated costimulation is necessary to induce human alloantigen-specific<br />
anergy: a method to ameliorate graft-versus-host disease<br />
and extend the donor pool. Blood 1996; 87: 4887-4893.<br />
27. Blazar BR, Taylor PA, Linsley PS et al. In vivo blockade of CD28/CTLA4:<br />
B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host<br />
disease across the major histocompatibility complex barrier<br />
in mice. Blood 1994; 83: 3815-3825.<br />
28. Przepiorka D, Kernan NA, Ippoliti C et al. Daclizumab, a humanized<br />
anti-interleukin-2 receptor alpha chain antibody, for treatment of acute<br />
graft-versus-host disease. Blood 2000; 95: 83-89.<br />
29. Williamson E, Garside P, Bradley JA et al. Neutralizing IL-12 during induction<br />
of murine acute graft-versus-host disease polarizes the cytokine<br />
profile toward a Th2-type alloimmune response and confers long term<br />
protection from disease. J Immunol 1997; 159: 1208-1215.<br />
30. Hill GR, Teshima T, Gerbitz A et al. Differential roles of IL-1 and<br />
TNF-alpha on graft-versus-host disease and graft versus leukemia. J Clin<br />
Invest 1999; 104: 459-467.<br />
31. Krijanovski OI, Hill GR, Cooke KR et al. Keratinocyte growth factor separates<br />
graft-versus-leukemia effects from graft-versus-host disease.<br />
Blood 1999; 94: 825-831.<br />
32. Panoskaltsis-Mortari A, Lacey DL, Vallera DA et al. Keratinocyte growth<br />
factor administered before conditioning ameliorates graft-versus-host<br />
disease after allogeneic bone marrow transplantation in mice. Blood<br />
1998; 92: 3960-3967.<br />
33. Locatelli F, Rondelli D,Burgio GR. Tolerance and hematopoietic stem<br />
cell transplantation 50 years after Burnet’s theory. Exp Hematol 2000;<br />
28: 479-489.<br />
34. Guinan EC, Boussiotis VA, Neuberg D et al. Transplantation of anergic<br />
histoincompatible bone marrow allografts [see comments]. N Engl J<br />
Med 1999; 340: 1704-1714.<br />
35. Sakurai J, Ohata J, Saito K et al. Blockade of CTLA-4 signals inhibits<br />
Th2-mediated murine chronic graft-versus-host disease by an enhanced<br />
expansion of regulatory CD8 + T cells. J Immunol 2000; 164: 664-669.<br />
36. Durie FH, Aruffo A, Ledbetter J et al. Antibody to the ligand of CD40,<br />
gp39, blocks the occurrence of the acute and chronic forms of<br />
graft-vs-host disease. J Clin Invest 1994; 94: 1333-1338.
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