Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor

Abstract

Graft-versus-host disease (GVHD), due to the presence of recipient-reactive T cells, limits the usefulness of bone marrow transplantation (BMT) and is a major contributor to patient mortality. To prevent GVHD, murine and human T cells were activated by antigen or mitogens and treated with a genetically engineered form of Pseudomonas exotoxin A (PE) directed against the IL-2 receptor. Treatment with the chimeric toxin eliminated alloreactive cytotoxic T lymphocytes (CTL) as determined by cytotoxicity and mixed lymphocyte culture assays. Precursor frequencies of alloreactive cytotoxic T cells and proliferative T cells were reduced up to 100-fold as shown by limiting dilution assays. Flow cytometric analyses revealed that treatment with the chimeric toxin completely eliminated CD25+ cells from the cultures. Toxin treatment had no significant effect on hematopoietic stem and progenitor cells as determined in vitro by colony-forming assays and in vivo by long-term hematopoietic recovery after 950 rad irradiation. Toxin treatment decreased GVHD in transplanted mice to less than 10% (as compared to 88% in untreated controls). Thus, it is possible to prevent life-threatening GVHD after BMT by using a CD25 receptor-directed toxin to eliminate host-reactive T cells from bone marrow grafts.

CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans

“…Although the depletion of total CD3 ϩ T cells is associated with an increased risk for infection and relapse, 40 because of the loss of antigen-specific T cells capable of mediating protective immune responses to pathogens 41 and leukemiaspecific antigens, 42 the depletion of a minor activated T-cell subset would still leave most of the TCR repertoire intact in the donor graft. In murine models 43 and in human preclinical trials, [44][45][46] the ex vivo depletion of CD25 ϩ donor T cells after stimulation with recipient alloantigens using a toxin-conjugated CD25-specific mAb has been shown to limit the development of GVHD after SCT. To our knowledge, the depletion of CD25-expressing T cells without alloantigenic stimulation has not been tested as a strategy to limit GVHD.…”

Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation

“…Responder cells obtained after allodepletion also maintain antitumor [19][20][21] and antiviral activity. [22][23][24] This promising approach has been validated in a number of centers in animal models, [25][26][27][28][29] and results of a trial in haploidentical peripheral blood stem cell transplantation (PBSCT) in pediatric patients suggest that the concept is feasible. 30,31 Encouraged by these preliminary findings, we tested the hypothesis that selective depletion (SD) of donor lymphocytes from the transplant ex vivo can reduce the risk of clinically significant GVHD.…”

The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality

“…Anti-CD25 mAb was administered to the recipient before transplantation in an attempt to avoid depletion of host-reactive donor T cells that would up-regulate CD25 as an activation marker during GVHD. Although CD25 depletion after BM transplantation has been shown to ameliorate GVHD, [28][29][30][31] CD25 depletion of the recipient before transplantation accelerated GVHD implicating host CD25 ϩ cells as involved in dampening the GVHD response. Although the goal was to deplete host CD25 ϩ cells and the last anti-CD25 mAb injection was given 4 days prior to transplantation, we cannot exclude the possibility that there was sufficient circulating antibody to deplete both host and donor CD25 ϩ cells including donor CD4 ϩ CD25 ϩ regulatory cells.…”