Hematopoietic Chimerism and Donor-specific Skin Allograft Tolerance After Nongenotoxic CD117 Antibody-drug-conjugate Conditioning in MHC-mismatched Allotransplantation
Li Z, Czechowicz A, Scheck A, et al. Nat Commun. 2019;10:616.
Selective Hematopoietic Stem Cell Ablation Using CD117-Antibody-drug-conjugates Enables Safe and Effective Transplantation With Immunity Preservation
Czechowicz A, Palchaudhuri R, Scheck A, et al. Nat Commun. 2019;10:617.
Hematopoietic stem cell (HSC) transplantation is a success story of cellular therapy for the cure of hematological malignancies, hemoglobinopathies, as well as immune pathologies.1 However, HSC transplantation is limited by the requirement for conditioning regimens that are cytotoxic and associated with significant risks including organ damage, mucositis, secondary malignancies, life-threatening infections, and graft-versus-host disease. These conditioning regimens are largely centered on total body irradiation or chemotherapy before transplantation to produce a bone marrow niche for engraftment. There is an urgent need to develop conditioning protocols that produce a more favorable balance between HSC engraftment the off-target effects of leukodepletion. A promising possibility is the specific targeting of recipient HSCs using monoclonal antibodies to produce “space” for donor HSC engraftment while maintaining remaining mature leukocytes.
A promising approach is to specifically target HSCs using a monoclonal antibody directed against CD117 (c-Kit), a receptor tyrosine kinase that is highly expressed on HSCs. In previous reports, the use of an anti-CD117 antibody has not been successful in wild type mice. However, when combined with a saporin-conjugated anti-CD45 immunotoxin, HSC engraftment has been effective, at least across a syngeneic transplant protocol.2 In two recent studies published in Nature Communications, a saporin-based CD117 antibody-drug-conjugate (CD117-ADC) has been assessed. In both studies, CD117-ADC resulted in depletion of recipient HSCs, enabling donor cell engraftment. Czechowicz et al show that mature leukocytes are not targeted by CD117-ADC, preserving immunity against a lymphocytic choriomeningitis virus infection across a syngeneic HSC transplantation model. Li et al extend the work to an allotransplantation model, showing that CD117-ADC treatment enables the engraftment of allogeneic HSCs. Moreover, engraftment results in chimerism that promotes donor-specific skin allograft tolerance. In the former study, Czechowicz et al also show that using a human CD117-ADC, human HSCs are depleted in a humanized mouse model.
Both studies provide compelling complementary data that argue for the use of targeted HSC depletion in conditioning regimens for HSC allotransplantation. The approach may also represent a useful adjunctive tool for experimental studies in which selective HSC depletion is required.
1. Gratwohl A, Pasquini MC, Aljurf M, et al; Worldwide Network for Blood and Marrow Transplantation (WBMT). One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2:e91–100.
2. Palchaudhuri R, Saez B, Hoggatt J, et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol. 2016;34:738–745.
Three Types of Functional Regulatory T Cells Control T Cell Responses at the Human Maternal-fetal Interface
Salvany-Celades M, van der Zwan A, Benner M, et al. Cell Rep. 2019;27:2537–2547.e5.
The idea of immunological tolerance was first recognized with the seminal work of Billingham et al1 and Owen2 in their studies of cattle twins and later of actively acquired tolerance in mice. Fetuses express foreign antigens that would normally be subject to an immune response directed to paternal alloantigen and self-antigens that are expressed only during embronic development (eg, carcinoembryonic antigen).3 The fetus is not completely physically isolated from the maternal immune system, and there is evidence for the development of an adaptive immune response during pregnancy.4 In fact, pregnancy is a known sensitizer and causative factor in the development of anti-HLA antibodies that can be detrimental in transplantation.5
Mechanisms responsible for suppression of antifetal responses that might otherwise result in an aborted pregnancy are not simply due to the physical fetal-maternal placental barrier, but due to active cellular mechanisms that may be discerned in mixed lymphocyte reactions. FOXP3+ regulatory T cells (Treg) are at least partly responsible for maintaining maternal-fetal tolerance and are found in high numbers in decidual tissues.6 In some experimental models, depletion of Treg results in pregnancy resorption, highlighting the importance of this cell population in maintaining allogeneic pregnancies. The relevance of the various Treg subtypes that are present, however, is currently lacking.
Salvany-Celades et al present an in-depth characterization of human decidual Treg types. Using flow cytometry, 3 separate populations were investigated: CD25hiFOXP3+, PD1hiIL-10+, and TIGIT+FOXP3dim. On isolation, all 3 populations were found to suppress both the proliferation and cytokine production of both CD4+ and CD8+ effector T cells in vitro. Interestingly, extra-villous trophoblasts as well as decidual macrophages isolated from the first-trimester placental tissue were able to increase the proportion of FOXP3+ Treg when cocultured with peripheral blood CD4+ T cells. Extra-villous trophoblasts (but not macrophages) increased PD1hi Treg with neither population having an effect on TIGIT+ Treg.
Overall, this study provides additional clarity to the fascinating tolerogenic mechanisms that are active during pregnancy in addition to the powerful role Treg play in maintaining immune homeostasis when needed. Understanding how these cells function in “nature’s transplant” provides opportunities to harness their suppressive mechanisms therapeutically in the development of tolerogenic therapies for transplantation.
1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172:603–606.
2. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945;102:400–401.
3. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7:241–246.
4. Pearson H. Reproductive immunology: immunity’s pregnant pause. Nature. 2002;420:265–266.
5. Brook MO, Wood KJ, Jones ND. The impact of memory T cells on rejection and the induction of tolerance. Transplantation. 2006;82:1–9.
6. Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol. 2013;31:387–411.