Tolerance: pregnancy matters

In this issue of Blood, van Halteren and colleagues demonstrate that not only antigen-specific CD8⁺ CTLs, but also antigen-specific CD8⁺ T_regs can emerge during pregnancy and persist over time when mother and offspring differ for minor histocompatibility antigens.¹  The relative ratio between these 2 populations, either promoting aggression against allogeneic tissues or tumor cells or tolerance toward alloantigens, is of potential great relevance in the context of HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is largely used for treating patients affected by many malignant hematologic disorders.²  The success of allo-HSCT is strictly dependent on the balance between the detrimental, sometimes fatal, attack of donor immune cells against normal recipient's tissues (ie, graft-versus-host disease [GVHD]) and the favorable reaction of donor lymphocytes toward malignant cells (ie, graft-versus-tumor [GVT] effect). While a large part of the GVT effect is related to the occurrence of GVHD, there is clear evidence that a selective effect of donor adaptive immunity on tumor cells can occur after allo-HSCT even without GVHD.³  This specific GVT effect is thought to be either directed against antigens with a tissue-restricted distribution (on hematopoietic cells in case of hematologic malignancies) or specifically preferentially expressed on tumor cells.⁴ 

Minor histocompatibility antigens (mHAgs) are polymorphic peptides encoded by genes located throughout the human genome, which can be presented by the major histocompatibility complex (MHC) molecules and recognized as a foreign antigen by T lymphocytes of a certain donor.⁵  These peptides can induce both donor–anti-host GVHD and GVT reactions, depending on their expression on both the nonhematopoietic cells and on normal and malignant hematopoietic cells of the recipient, respectively. The ultimate goal of allo-HSCT–based immunotherapy is to maximize the GVT response while mitigating collateral damage to normal tissues by GVHD. Dissecting the role of different mHAgs in the elicitation of these effects has also been an area of active investigation in recent years.

Pregnancy is characterized by a bidirectional trafficking of both fetal and maternal cells, leading to different levels of microchimerism both in the mother and in the offspring. These circulating cells may stimulate reciprocal immune sensitization, resulting in the generation of mHAg-specific cytotoxic T lymphocytes (CTLs).⁶  For example, this phenomenon accounts for the increased risk of immune complications and transplantation-related mortality, observed when a parous female is used as allo-HSCT donor for a male recipient.⁷  In their article in this issue of Blood, van Halteren and colleagues provide sound evidence that mHAg-specific CD8⁺ regulatory T cells (T_regs) can also emerge during pregnancy and persist for many years. Although the precise mechanism leading to the preferential emergence of either mHAg-specific CD8⁺ CTLs or T_regs remains obscure deserving further investigation, this observation may have relevant clinical implications in allo-HSCT from both HLA-matched and disparate donors. Indeed, in donor/recipient allo-HSCT pairs differing for mHAgs, either severe acute GVHD or a potent GVT effect could be predicted to occur if the donor shows a prevalence of mHAg-specific CD8⁺ CTLs. Conversely, donors with prevalence of mHAg-specific CD8⁺ T_regs should represent a safeguard toward the risk of life-threatening GVHD, although potentially increasing the risk of leukemia relapse as a blunting effect of T_regs against tumor cells has been recognized as one of the mechanisms of immune escape.⁸  It is reasonable that this specific balance be of greater clinical relevance in the context of unmanipulated allo-HSCT and when the donor is HLA-matched rather than disparate with the recipient.

The intriguing immunobiologic translations deriving from the results reported by van Halteren et al will find routine clinical application when less cumbersome and more standardized in vitro methods become available for a precise and reliable identification of either CTLs or T_regs. For the time being, this piece of information, together with the demonstration that during pregnancy a preferential induction of CD4⁺ T_regs lymphocytes occurs in fetal lymph nodes and spleen,⁹  contributes to biologically explain the clinical advantages deriving from using either the mother as donor in T cell–depleted, haploidentical transplantations¹⁰  or an HLA-mismatched sibling disparate for noninherited maternal antigens.¹¹ 

There is one last potential translation for the evaluation of the balance between mHAg-specific CTLs or T_regs. Cellular adoptive immunotherapy based on the use of mHAg-specific CTLs directed against hematopoietic tissue–restricted antigens, such as HA-1 and HA-2, has been proposed for preventing/treating leukemia relapse occurring after an allograft.¹²  It is evident that the data produced by van Halteren et al render the evaluation of the presence of these mHAg-specific CD8⁺ T_regs in the donor more than opportune to optimize the chance of success of adoptive cell therapy.

There is still much more to learn about tolerogenic versus immunogenic fetal/maternal interactions, but there is no doubt that pregnancy and allo-HSCT share commonalities.