Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation

Abstract

During pregnancy women can develop B-and T-cell immunity against the inherited paternal antigens (IPAs) of the fetus, such as HLA, peptides of minor histocompatibilty antigens, and possibly oncofetal antigens. The biological and pathological role of these pregnancy-induced immunological events is only understood in part. However, anti-IPA immunity in the mother persists for many decades after delivery and may reduce relapse in offspring with leukemia after HLA-haploidentical transplantation of maternal hematopoietic stem cells (HSC). We hypothesized that maternal anti-IPA immune elements cross the placenta and might confer a potent graft-versusleukemia effect when cord blood (CB) is used in unrelated HSC transplantation. In a retrospective study of single-unit CB recipients with all grafts provided by the New York Blood Center, we show that patients with acute myeloid or lymphoblastic leukemia (n = 845) who shared one or more HLA-A, -B, or -DRB1 antigens with their CB donor's IPAs had a significant decrease in leukemic relapse posttransplantation [hazard ratio (HR) = 0.38, P < 0.001] compared with those that did not. Remarkably, relapse reduction in patients receiving CB with one HLA mismatch (HR = 0.15, P < 0.001) was not associated with an increased risk of severe acute graft-versus-host disease (HR = 1.43, P = 0.730). Our findings may explain the unexpected low relapse rate after CB transplantation, open new avenues in the study of leukemic relapse after HSC transplantation (possibly of malignancies in general), and have practical implications for CB unit selection.cord blood stem cell transplantation | birth order

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…However, cord blood as a stem cell source may also have an intrinsically enhanced GvL effect. 49 Methylprednisolone has been shown to induce not only NK cell maturation but also to impair their cytotoxicity in vitro. 50,51 In vivo, prophylactic corticosteroids seemed to alter NK cell recovery after HSCT.…”

Microchimerism in cord blood: Mother as anticancer drug

“…The findings of van Rood et al (3) suggest that anti-IPA immunity is of value in cancer immunotherapy. Beyond CB transplantation, this type of stealth immune function is inherent in all outbred individuals because of MMc.…”

“…By transferring the fetal-maternal battlefront to the leukemia patient's own battle with cancer, oncologists have unwittingly tapped into a rich source of graft vs. leukemia activity. Now that the secret is out, thanks to the work by van Rood et al (3), it would be wise to type mothers routinely, determine the IPAs, and avoid transplants in which the recipient does not share these IPAs with the CB donor.…”

Fetal maternal immunity and antileukemia activity in cord-blood transplant recipients

“…Although CB grafts consist primarily of fetal cells, some maternal cells are present. 10,11 Indirect evidence reported by van Rood et al 8 strongly implicates maternal immune cells with anti-IPA activity in the GVL effect observed with CBT. Maternal cells are implicated because relapse was reduced specifically when the transplant recipient had one or more HLA antigens that were the same as an IPA of the CB donor.…”

“…Interestingly, a recent study suggests maternal cells in CB grafts that are sensitized to fetal inherited paternal antigens (IPAs) (Figure 1a) may also contribute to the lower incidence of relapse. 8 Fetal exposure to noninherited maternal HLA antigens (NIMA) (Figure 1b) is thought to produce tolerance to NIMA, and improved outcome was previously reported when NIMA of the CB donor was shared by a recipient. 9 On the other hand, during pregnancy women develop B-and T-cell immunity against fetal histocompatibility antigens and minor histocompatibility antigens that are paternally-inherited.…”