Immunological considerations in in utero hematopoetic stem cell transplantation (IUHCT)

Abstract

In utero hematopoietic stem cell transplantation (IUHCT) is an attractive approach and a potentially curative surgery for several congenital hematopoietic diseases. In practice, this application has succeeded only in the context of Severe Combined Immunodeficiency Disorders. Here, we review potential immunological hurdles for the long-term establishment of chimerism and discuss relevant models and findings from both postnatal hematopoietic stem cell transplantation and IUHCT.

Keywords: central tolerance; fetal alloresponse; in utero hematopoetic stem cell transplantation; maternal alloresponse; regulatory T cells (T-Regs).

Figure 1

Mixed Lymphocyte Reactions (MLR) with central tolerant or peripheral tolerant lymphocyte populations from IUHCT graft recipients. Recipients of IUHCT carry mixed hematopoietic chimerism. (A,B) In central tolerance, thymic selection will only allow recipient T cells that are non-recipient and non-donor specific to persist (yellow/green cells). Similarly, donor cells are only allowed to persist if they are non-recipient and non-donor specific (blue/yellow cells). Exposure of these two responder populations to irradiated donor cells will not elicit a proliferative response (A) even after the deletion of Tregs (B). (C,D) In peripheral tolerance, recipient T cells with specificity for the donor are allowed to progress through thymic selection into the periphery (Green/blue cells) but effector functions and proliferation are inhibited by Tregs (Green/pink cells). Exposure of these three responder populations to donor cells will not result in proliferation (C). After the deletion of Tregs, the recipient T cells with donor specificity will proliferate vigorously in response to donor cells (D). Note: It is unknown whether the Tregs are donor-derived or recipient-derived or both.

Figure 2

Cortical thymic T cell selection. (A) Chimeric bone marrow can give rise to multiple blood products from the two stem cell sources (recipient: green, donor: blue) such as antigen-presenting cells (APC) and thymocytes (B) In the thymic cortex, productive interaction with the MHC takes place. Though knowledge is limited, cortical Thymic Epithelial Cells (cTEC) likely will be recipient-derived (C–F, green cTEC cell). In contrast, APC are constantly turned over and immigrate from the periphery theoretically allowing for the participation of donor-derived APC in the thymic selection process (D,F). Therefore, donor thymocytes can interact with recipient cTEC and recipient APC and hence recipient MHC to receive survival signals (C) or with recipient cTEC and donor APC hence interacting with donor APC (D) Conversely, recipient thymocytes can interact with recipient cTEC and recipient APC and hence recipient MHC to receive survival signals (E) or with recipient cTEC and donor APC hence interacting with donor APC (D) The source of the peptides during this process (recipient or donor) is unknown.

Figure 3

Thymic medullary selection. In the second step of thymic selection, T cells are selected for the absence of high affinity self-peptide-self-MHC reactivity. Chimeric bone marrow (A) can give rise to multiple blood products from the two stem cell sources (recipient: green, donor: blue) such as antigen-presenting cells (APC) and thymocytes (B) While the Medullary Thymic Epithelial Cells (mTEC) are recipient derived (green mTEC, C), medullary APC can be either recipient derived (green, left) or donor derived (blue, right) and all of these cells can either present recipient (green) or donor derived (blue) peptides on their respective MHC. Combined with thymocytes of either recipient or donor origin, several combinations of MHC-peptide-TCR reactivity are possible (D) of which those with high affinity will be deleted (E) intermediate reactivity will develop into tTregs and low affinity will develop into conventional T cells of the CD4 or CD8 lineage.

Figure 4

Graft-vs. host and host-vs. graft disease. Graft-vs. host disease or graft-vs. leukemia effect is based on the same anti-host reactivity of the graft lymphocytes (top panels). Recipient (green centers) and donor (blue centers) cells undergo thymic selection, and donor T cells with recipient specificity escape into the periphery (lowest row of top panel). These recipient-reactive cells will delete leukemia cells and other host lymphocytes in the periphery. In severe cases, graft-vs. host disease develops and recipient tissues such as the kidney are attacked. The extent of recipient-specific effector cells attacking recipient T cells already in the thymus or HSC in the bone marrow is unknown. Host-vs. graft reactions (lower panels) are the basis of graft rejection in which recipient T cells with donor specificity escape thymic deletion and attack donor cells. While it is known that ultimately disappear from the bone marrow in this case, it is unclear whether this is due to direct deletion by donor-specific recipient cells or another mechanism.

Figure 5

Non-inherited maternal antigens (NIMAs). Central tolerance includes tolerance toward antigens that the fetus inherited from both mother and father (top panels). Maternal cells inhabiting the fetus bring along additional antigens that were not inherited by the fetus (middle panel, left hand side symbols on the maternal cell). The presence of these antigens induces fetal Tregs specific for these NIMAs (middle panels, yellow cell on the right). When donor cells carry NIMAs, these fetal Tregs will suppress allo-reactions (lower panels), an effect that can be either detrimental or desirable.