In this issue, 2 papers extend these observations. Miklos and colleagues (page 353) looked for antibodies against the well-defined Y-chromosome–encoded dead box RNA helicase Y (DBY) protein by Western blot analysis and enzyme-linked immunosorbent assay (ELISA) techniques. They found antibodies against DBY in 50% of male patients who received stem cell grafts from female donors. The same antibodies were detected in about 15% to 20% of healthy females, but were not found in healthy males. Antibody responses were primarily directed against areas of amino acid disparity between DBY and its female homologous counterpart DBX. Clearly, the Y-linked DBY protein can trigger a B-cell–mediated immune response. Randolph and colleagues (page 347) analyzed 3238 individuals who received HLA-identical sibling HSC transplants for various hematologic malignancies and looked at incidence of GVHD and relapse. GVHD was, as expected, higher in male recipients of female grafts. The same recipients did exhibit a lower hazard of relapse compared with other sex combinations. This graft-versus-leukemia effect (GVL) was preserved even after controlling for GVHD as a time-dependent covariate. Hence, Y-antigen–encoded gene products can act as minor histocompatibility antigens and trigger rejection, GVHD, and GVL. These Y-chromosome–associated effects reflect the full repertoire of the immune response.
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These observations have direct clinical consequences. Donor-recipient sex combination has to be considered in any donor-selection algorithm. Rejection is primarily of concern when transplantation is planned for aplastic anemia or congenital disorders. If there is a choice, a male donor for female recipient should not be selected. The decision is more complex in hematologic malignancies. Transplantation-related mortality is more of a concern than rejection. In the past, the strategy was clear: a female donor for a male recipient was to be avoided.4 The decision has now become more difficult. In the short term, survival is worse for males with female grafts. The detrimental effect of GVH reaction is, early after HSCT, higher than the benefit from GVL. However, if with longer follow-up the GVL benefit outweighs early loss, we might have to reconsider the decisions of today.
The findings raise even more intriguing questions. What are the mechanisms behind the recognition of male gene products by women? If nearly 20% of healthy women and 50% of male recipients of female transplants have anti-Y antibodies, why are the clinical consequences so rare? Why are so many HLA-identical sex-mismatched transplants accepted with no rejection? Why are male fetuses safe during pregnancy? There is a hint to these questions in the work of Miklos et al. In all situations when they were able to identify the peptide sequences, there was a difference between the male DBY and female DBX protein. It is unknown whether the differences in these peptides represent spontaneous mutations or a basic inherent sex-linked difference. Obviously, we received clear answers but are left with many open questions.
References
- Uphoff DE. Comparative survival of lethally irradiated inbred male mice inoculated with marrow from virgin or multiparous female donors. J Natl Cancer Inst. 1975;54: 1343-1347.
- Spierings E, Vermeulen CJ, Vogt MH, et al. Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet. 2003; 362: 610-615.
- Zwaan FE, Hermans J, Gratwohl A, for the EBMT Leukaemia Party (EBMT-LWP). The influence of donor-recipient sex mismatching on the outcome of allogeneic BMT in leukemia. Bone Marrow Transplant. 1989;4(suppl 2): 8.
- Gratwohl A, Hermans J, Goldman JM, et al, for the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet. 1998;352: 1087-1092.
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