CTLA4Ig TREATMENT AMELIORATES THE LETHALITY OF MURINE GRAFT-VERSUS-HOST DISEASE ACROSS MAJOR HISTOCOMPATIBILITY COMPLEX BARRIERS

135

4-1BB is expressed on activated CD4+ and CD8+ T cells; its ligand, 4-1BB ligand is expressed on APCs. Despite expression on both T cell subpopulations, 4-1BB has been reported to predominantly affect CD8+ T cell responses. By quantifying graft-vs-host disease alloresponses in vivo, we demonstrate that both CD4+ and CD8+ T cell-mediated alloresponses are regulated by 4-1BB/4-1BB ligand interactions to approximately the same extent. 4-1BB receptor-facilitated CD4+ T cell-mediated alloresponses were partly CD28 independent. In two distinct marrow graft rejection systems, host CD8+ and CD4+ T cells each separately contributed to host anti-donor T cell-mediated allograft rejection. α4-1BB mAb increased the graft-vs-leukemia effect of a suboptimal number of donor splenocytes given later post bone marrow transplantation by bolstering allogeneic responses resulting in leukemia elimination. In summary, 4-1BB ligation is a potent regulator of CD4+ and CD8+ T cell-mediated allogeneic responses in vivo. Modifying the ligation of 4-1BB represents a new approach to altering the graft-vs-host disease and graft-vs-leukemia effects of allogeneic T cells post bone marrow transplantation.

Section: Discussionmentioning

confidence: 85%

Section: Despite the Expression Of 4-1bb On Both Cd4mentioning

confidence: 99%

Ligation of 4-1BB (CDw137) Regulates Graft-Versus-Host Disease, Graft-Versus-Leukemia, and Graft Rejection in Allogeneic Bone Marrow Transplant Recipients

Blazar

Kwon

Panoskaltsis‐Mortari

et al. 2001

135

“…Prior to human application, effects of blockade of the CD28/B7 and the CD40/CD40L interaction have been extensively studied in experimental settings of alloresponses such as graft-versushost disease (GVHD) or transplant rejection. In a fully MHCmismatched mouse model of GVHD, either anti-B7 mAb or CTLA-4Ig clearly reduced lethality (5,6), and anti-CD40L mAb improved the outcome of GVHD in mice (7). However, occurrence and progression of GVHD could not be completely inhibited in these studies with single-pathway costimulation blockade.…”

mentioning

confidence: 83%

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Vogel

Verbinnen

Gool

et al. 2016

Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4+ T cells, or CD8+ T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4+ T cells, but not of CD8+ T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8+ T cells but had only a weak effect on CD4+ T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4+ and CD8+ T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.

“…The expressed protein includes aa 4 -299 of the mature protein. Murine CTLA4Ig and a control fusion protein, L6, were prepared as previously described (22). Hamster IgG antimouse B7-1 mAb (16-10A1) (23) and rat IgG2a anti-mouse B7-2 mAb (GL1) (24) were purified from culture supernatant using a protein G column.…”

Section: Reagentsmentioning

confidence: 99%

B7 Requirements for Primary and Secondary Protein- and Polysaccharide-Specific Ig Isotype Responses toStreptococcus pneumoniae

Wu¹,

Khan²,

Shen³

et al. 2000

The requirements for B7 costimulation during an in vivo humoral response to an intact extracellular bacteria have not been reported. In this study we immunized mice with Streptococcus pneumoniae (R36A) to determine the B7 requirements for induction of Ig, specific for two determinants on R36A, the phosphorylcholine (PC) determinant of C-polysaccharide and pneumococcal surface protein A (PspA). We show that the primary anti-PspA response, the development of PspA-specific memory, and the induction of the secondary anti-PspA response in primed mice were completely dependent upon B7 costimulation. Of note, costimulation was required only briefly after the secondary immunization compared with after the primary immunization for optimal induction of Ig. Blockade of B7 costimulation at the time of secondary immunization also completely abrogated the established state of memory, but did not induce tolerance. In contrast to the anti-PspA response, the primary anti-PC response involved only a very short period of B7 costimulation. Whereas B7-2 alone was required for induction of the primary anti-PspA and anti-PC responses, a redundant role for B7-1 and B7-2 was noted for the PspA-specific secondary response. CTLA4Ig blocked both the anti-PC and anti-PspA responses equally well over a wide range of bacterial doses. These studies demonstrate a critical, but variable, role for B7-dependent costimulation during an Ig response to an extracellular bacteria.