CD28 Blockade Ex Vivo Induces Alloantigen-Specific Immune Tolerance but Preserves T-Cell Pathogen Reactivity

Abstract

Donor T-cells contribute to reconstitution of protective immunity after allogeneic hematopoietic stem cell transplantation (HSCT) but must acquire specific tolerance against recipient alloantigens to avoid life-threatening graft-versus-host disease (GvHD). Systemic immunosuppressive drugs may abrogate severe GvHD, but this also impedes memory responses to invading pathogens. Here, we tested whether ex vivo blockade of CD28 co-stimulation can enable selective T-cell tolerization to alloantigens by facilitating CD80/86-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling. Treatment of human allogeneic dendritic cell/T-cell co-cultures with a human CD28 blocking antibody fragment (α-huCD28) significantly abrogated subsequent allospecific immune responses, seen by decreased T-cell proliferation and of type 1 cytokine (IFN-γ and IL-2) expression. Allo-tolerization persisted after discontinuation of CD28 blockade and secondary alloantigen stimulation, as confirmed by enhanced CTLA-4 and PD-1 immune checkpoint signaling. However, T-cells retained reactivity to pathogens, supported by clonotyping of neo-primed and cross-reactive T-cells specific for Candida albicans or third-party antigens using deep sequencing analysis. In an MHC-mismatched murine model, we tolerized C57BL/6 T-cells by ex vivo exposure to a murine single chain Fv specific for CD28 (α-muCD28). Infusion of these cells, after α-muCD28 washout, into bone marrow-transplanted BALB/c mice caused allo-tolerance and did not induce GvHD-associated hepatic pathology. We conclude that selective CD28 blockade ex vivo can allow the generation of stably allo-tolerized T-cells that in turn do not induce graft-versus-host reactions while maintaining pathogen reactivity. Hence, CD28 co-stimulation blockade of donor T-cells may be a useful therapeutic approach to support the immune system after HSCT.

Nsp1α of Porcine Reproductive and Respiratory Syndrome Virus Strain BB0907 Impairs the Function of Monocyte-Derived Dendritic Cells via the Release of Soluble CD83

“…During viral infection, MoDCs change cytokine secretion levels and alter the expression of major histocompatibility complex (MHC) proteins and costimulatory molecules on the cell surface (25,26). The MHC has a critical role in the immune response against viral infections, as MHC class I (MHC-I) molecules function in antigen presentation on the cell surface for T cell recognition (27)(28)(29). The MHC class I complex consists of three main subunit structures, which together enable the escape of immune proteins from the endoplasmic reticulum (ER) to the cell surface.…”

Treatment of mice with a ligand binding blocking anti-CD28 monoclonal antibody improves healing after myocardial infarction

“…Hence, attenuated T-cell and macrophage driven local inflammation might most likely both have contributed to the beneficial effect of the anti-CD28 mAb treatment approach. PLOS ONE [25,26] conventional T-cell activation, as tested here, or superagonistic anti-CD28 mAbs which are boosting the Foxp3 + T-cell compartment, have been tested in early clinical studies and proved to be save [27]. The superagonistic mAb approach has been shown to be beneficial in experimental myocardial infarction models before [18,28].…”

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

“…albicans or third-party-specific reactions in re-stimulation cultures. 40 Phase 1 data and available ex-vivo data therefore indicate that exposure to viral and fungal pathogens while under CD28 antagonist treatment might not compromise immunity on the short term. In spite of these data, to our knowledge, no clinical experience has been gained so far in kidney transplant recipients with a CD28 antagonist.…”