Although anti-human leukocyte antigen antibodies (anti-HLA Abs) are important factors responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complications, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been finally defined. Enormous polymorphism of HLA-genes, their immunogenicity and heterogeneity of antibodies, as well as the growing number of allo-HSCTs from partially HLA-mismatched donors, increase the probability that anti-HLA antibodies could be important factors responsible for the treatment outcomes. We have examined the incidence of anti-HLA antibodies in a group of 30 allo-HSCT recipients from HLA-mismatched unrelated donors. Anti-HLA Abs were identified in sera collected before and after allo-HSCT. We have used automated DynaChip assay utilizing microchips bearing purified class I and II HLA antigens for detection of anti-HLA Abs. We have detected anit-HLA antibodies against HLA-A, B, C, DR, DQ and DP, but no donor or recipient-specific anti-HLA Abs were detected in the studied group. The preliminary results indicate that anti-HLA antibodies are present before and after allo-HSCT in HLA-mismatched recipients. 1. Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment of both congenital and acquired disturbances of hematopoiesis, especially of hematological malignancies. The selection of the optimal donor is based on high-resolution HLA typing. The MHC (Major Histocompatibility Complex) contains more than 200 genes which are situated on the short arm of chromosome 6 at 6p21.3. It is divided into three main regions: HLA class I (containing HLA-A, B, and C genes), class II (containing HLA-DR, DQ, and DP genes), and class III region. The role of HLA molecules is to present peptides to T cells (both CD4 and CD8 T cells), enabling them to recognize and eliminate “foreign” particles and also to prevent the recognition of “self” as foreign. HLA mismatches may occur at antigenic or allelic level; the first are characterized by amino acid substitutions in both peptide-binding and T-cell recognition regions, whereas the latter are characterized by amino-acid substitution in the peptide binding regions only [1]. HLA antigens are recognized by immunocompetent T cells, what may lead to graft failure, graft versus host disease (GVHD), and other posttransplant complications as well as to favorable graft versus leukemia (GVL) effect. HLA molecules bear multiple antigenic epitopes, many of which are the so-called “public” epitopes
References
[1]
J. Apperley, E. Carreras, E. Gluckman, and T. Masszi, Haematopoietic Stem Cell Transplantation-The EBMT Handbook, 6th edition, 2012.
[2]
F. Legrand and J. Dausset, “Serological evidence of the existence of several antigenic determinants (or factors) on the HLA-A gene products,” in Histocompatibility Testing 1972, J. Dausset and J. Colombani, Eds., Munksgaard, Copenhagen, Denmark, 1973.
[3]
G. E. Rodey and T. C. Fuller, “Public epitopes and the antigenic structure of the HLA molecules,” Critical reviews in immunology, vol. 7, no. 3, pp. 229–267, 1987.
[4]
B. D. Schwartz, L. K. Luehrman, and G. E. Rodey, “Public antigenic determinant on a family of HLA-B molecules. Basis for cross-reactivity and a possible link with disease predisposition,” Journal of Clinical Investigation, vol. 64, no. 4, pp. 938–947, 1979.
[5]
R. A. Rhoades and R. G. Pflanzer, Human Physiology, Thomson Learning, Stockholm, Sweden, 4th edition, 2002.
[6]
J. Charles, Immunobiology, Garland Publishing, New York, NY, USA, 5th edition, 2001.
[7]
L. J. Fanning, A. M. Connor, and G. E. Wu, “Development of the immunoglobulin repertoire,” Clinical Immunology and Immunopathology, vol. 79, no. 1, pp. 1–14, 1996.
[8]
P. Peter, The Immune System, Garland Science, New York, NY, USA, 2nd edition, 2005.
[9]
Y. Bergman and H. Cedar, “A stepwise epigenetic process controls immunoglobulin allelic exclusion,” Nature Reviews Immunology, vol. 4, no. 10, pp. 753–761, 2004.
[10]
M. Or-Guil, N. Wittenbrink, A. A. Weiser, and J. Schuchhardt, “Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation,” Immunological Reviews, vol. 216, no. 1, pp. 130–141, 2007.
[11]
N. El-Awar, P. I. Terasaki, A. Nguyen et al., “Epitopes of human leukocyte antigen class I antibodies found in sera of normal healthy males and cord blood,” Human Immunology, vol. 70, no. 10, pp. 844–853, 2009.
[12]
L. E. Morales-Buenrostro, P. I. Terasaki, L. A. Marino-Vázquez, J. H. Lee, N. El-Awar, and J. Alberú, “Natural human leukocyte antigen antibodies found in nonalloimmunized healthy males,” Transplantation, vol. 86, no. 8, pp. 1111–1115, 2008.
[13]
W. E. Braun, “Laboratory and clinical management of the highly sensitized organ transplant recipient,” Human Immunology, vol. 26, no. 4, pp. 245–260, 1989.
[14]
A. Idica, N. Sasaki, S. Hardy, and P. Terasaki, “Unexpected frequencies of HLA antibody specificities present in sera of multitransfused patients.,” Clinical transplants, pp. 139–159, 2006.
[15]
E. Hod and J. Schwartz, “Platelet transfusion refractoriness,” British Journal of Haematology, vol. 142, no. 3, pp. 348–360, 2008.
[16]
R. A. Middelburg, D. Van Stein, E. Bri？t, and J. G. Van Der Bom, “The role of donor antibodies in the pathogenesis of transfusion-related acute lung injury: a systematic review,” Transfusion, vol. 48, no. 10, pp. 2167–2176, 2008.
[17]
A. Reil, B. Keller-Stanislawski, S. Günay, and J. Bux, “Specificities of leucocyte alloantibodies in transfusion-related acute lung injury and results of leucocyte antibody screening of blood donors,” Vox Sanguinis, vol. 95, no. 4, pp. 313–317, 2008.
[18]
E. R. Vasilescu, E. K. Ho, A. I. Colovai et al., “Alloantibodies and the outcome of cadaver kidney allografts,” Human Immunology, vol. 67, no. 8, pp. 597–604, 2006.
[19]
A. A. Zachary, L. E. Ratner, J. A. Graziani, D. P. Lucas, N. L. Delaney, and M. S. Leffell, “Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: II. Clinical relevance,” Human Immunology, vol. 62, no. 3, pp. 236–246, 2001.
[20]
F. Kissmeyer-Nielsen, S. Olsen, V. P. Petersen, and O. Fjeldborg, “Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells.,” The Lancet, vol. 2, no. 7465, pp. 662–665, 1966.
[21]
G. M. Williams, D. M. Hume, R. P. Hudson Jr, P. J. Morris, K. Kano, and F. Milgrom, “Hyperacute renal-homograft rejection in man.,” New England Journal of Medicine, vol. 279, no. 12, pp. 611–618, 1968.
[22]
E. Schwartz, T. Lapidot, and D. Gozes, “Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors,” Journal of Immunology, vol. 138, no. 2, pp. 460–465, 1987.
[23]
D. A. Vallera and B. R. Blazar, “T cell depletion for graft-versus-host disease prophylaxis: a perspective on engraftment in mice and humans,” Transplantation, vol. 47, no. 5, pp. 751–760, 1989.
[24]
K. Fleischhauer, N. A. Kernan, R. J. O'Reilly, B. Dupont, and S. Y. Yang, “Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44,” New England Journal of Medicine, vol. 323, no. 26, pp. 1818–1822, 1990.
[25]
J. Pei, Y. Akatsuka, C. Anasetti et al., “Generation of HLA-C-specific cytotoxic T cells in association with marrow graft rejection: analysis of alloimmunity by T-cell cloning and testing of T-cell-receptor rearrangements,” Biology of Blood and Marrow Transplantation, vol. 7, no. 7, pp. 378–383, 2001.
[26]
S. M. Davies, C. Kollman, C. Anasetti et al., “Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program,” Blood, vol. 96, no. 13, pp. 4096–4102, 2000.
[27]
P. Rubinstein, C. Carrier, A. Scaradavou et al., “Outcomes among 562 recipients of placental-blood transplants from unrelated donors,” New England Journal of Medicine, vol. 339, no. 22, pp. 1565–1577, 1998.
[28]
C. Anasetti, K. C. Doney, and R. Storb, “Marrow transplantation for severe aplastic anemia. Long-term outcome in fifty 'untransfused' patients,” Annals of Internal Medicine, vol. 104, no. 4, pp. 461–466, 1986.
[29]
R. P. Warren, R. Storb, P. L. Weiden, P. J. Su, and E. D. Thomas, “Lymphocyte-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity in patients with aplastic anemia: distinguishing transfusion-induced sensitization from possible immune-mediated aplastic anemia.,” Transplantation Proceedings, vol. 13, no. 1, pp. 245–247, 1981.
[30]
Y. L. Colson, M. J. Schuchert, and S. T. Ildstad, “The abrogation of allosensitization following the induction of mixed allogeneic chimerism,” Journal of Immunology, vol. 165, no. 2, pp. 637–644, 2000.
[31]
P. A. Taylor, M. J. Ehrhardt, M. M. Roforth et al., “Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients,” Blood, vol. 109, no. 3, pp. 1307–1315, 2007.
[32]
R. J. Greenwald, G. J. Freeman, and A. H. Sharpe, “The B7 family revisited,” Annual Review of Immunology, vol. 23, pp. 515–548, 2005.
[33]
A. Bartholomew, D. Sher, S. Sosler et al., “Stem cell transplantation eliminates alloantibody in a highly sensitized patient,” Transplantation, vol. 72, no. 10, pp. 1653–1655, 2001.
[34]
S. Spellman, R. Bray, S. Rosen-Bronson et al., “The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure,” Blood, vol. 115, no. 13, pp. 2704–2708, 2010.
[35]
S. O. Ciurea, P. F. Thall, X. Wang et al., “Donor-specific anti-HLAAbs and graft failure in matched unrelated donor hematopoietic stem cell transplantation,” Blood, vol. 118, no. 22, pp. 5957–5964, 2011.
[36]
M. Takanashi, Y. Atsuta, K. Fujiwara et al., “The impact of anti-HLA antibodies on unrelated cord blood transplantations,” Blood, vol. 116, no. 15, pp. 2839–2846, 2010.
[37]
C. Cutler, H. T. Kim, L. Sun et al., “Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation,” Blood, vol. 118, no. 25, pp. 6691–6697, 2011.
