Another cause for incompatibility: gestational priming of women by tissue antigens of men

Allogeneic stem cell transplantation (SCT) has emerged as a major therapeutic for endstage blood cell diseases. However, graft-versus-host disease (GVHD), which results from the priming of donor T cells by the recipient's minor histocompatibility (H) antigens, is a serious, often fatal, impediment to the success of this otherwise life-giving procedure. Previous studies have shown an increased incidence of GVHD in recipients of female donor cells. Moreover, recipients of parous female donor SCs are at an increased risk for GVHD compared with those who receive cells from nulliparous female donors. In this issue of Blood, Verdijk and colleagues (page 1961) test the hypothesis that paternally derived fetal minor H antigens can prime parous donor T cells. They demonstrate the presence of both the Y chromosome and autosomally encoded minor H antigen–specific CD8⁺ T lymphocytes (CTLs) in healthy multiparous female donors. Curiously, only 4 of the 7 donors examined demonstrated this type of CTL priming. The donors were presumably exposed to these minor H antigens during pregnancy. The minor H antigen–specific CTLs examined had a memory phenotype, possibly remaining in circulation for up to 22 years after pregnancy. A similar finding was reported by James and colleagues¹  from their studies in the mouse model and from the analysis of HY-specific CTLs in a multiparous woman. The authors of both studies argue for a causal relationship between this gestational priming of CTLs and the increased incidence of GVHD, but such a relationship remains to be established. A systematic study of parous female donors as well as recipients before and after transplantation should provide insights into the role of preprimed minor H antigen–specific CTLs and clinical outcome following SCT.

From a basic human immunology point of view, it is curious that some multiparous women were not primed by male minor H antigens despite incompatibility. Was lack of priming due to holes in the T-cell repertoire or was it due to active suppression? Understanding why priming did not occur will pave the way to a better understanding of human immune response without invasive experimentation. It might also provide clues to the mechanism(s) underlying transplant tolerance. From a clinical standpoint, the presence of recipient minor H antigen–specific CTLs in donors has important implications. SC donors can be screened for the presence of recipient minor H antigen–specific CTLs by using tetramers of HLA class I bound with the different T-cell epitopes. Given the fact that the immunodominant human minor H antigens are encoded by dimorphic genes, potential donors can be screened for the expression of both major and minor H antigens. Perhaps even more intriguing is the possibility that precursor CTLs derived from multiparous female donors can be developed into therapeutics against tumor cells that express specific minor H antigens. Skeptics, stay tuned! Studies of minor H antigens in mice and men have much to offer to our understanding of basic and clinical human immunology.