Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation

Abstract

Aspergillus and cytomegalovirus are major causes of morbidity/mortality after haploidentical hematopoietic transplantation. The high degree of mismatching makes cell immunotherapy impossible as it would result in lethal graft-versus-host disease (GvHD). We generated large numbers of donor T-cell clones specific for Aspergillus or cytomegalovirus antigens. We identified clones potentially responsible for causing GvHD by screening them for cross-reactivity against recipient mononuclear cells. Nonrecipient reactive, pathogen-specific clones were infused soon after transplantation. They were CD4 ؉ and produced high levels of interferon-␥ and low levels of interleukin-10. In 46 control transplant recipients who did not receive adoptive therapy, spontaneous pathogen-specific T cells occurred in low frequency 9 to 12 months after transplantation and displayed a nonprotective low interferon-␥/high interleukin-10 production phenotype.

Clinical-scale generation of human anti-Aspergillus T cells for adoptive immunotherapy

“…22 Although we did not assess the capacity to damage hyphae of A. fumigatus, the CD4 þ T cells generated according to GMP conditions produced IFN-g upon restimulation with Aspergillus antigens, and thus most likely enhance the antifungal activity of phagocytes. 10 Our in vitro data also indicate a reduced alloreactivity of the generated antiAspergillus T cells and support the in vivo findings by Perruccio et al 16 who transferred ex vivo cultured and pathogen-specific T cells without triggering GVHD. In summary, we present a simple and rapid method for the clinical-scale generation of functionally active antiAspergillus T H 1 cells according to GMP conditions.…”

“…4,16 Importantly, several extracts prepared under identical conditions resulted in comparable numbers and function of the generated cells, indicating the reproducibility of our system (data not shown). In addition, extensive controls after stimulation, isolation and culture of anti-Aspergillus T cells did not reveal contamination with a pathogen or endotoxin.…”

“…In one clinical trial, 10 hematopoietic transplant recipients with evidence of invasive aspergillosis received antiAspergillus adoptive therapy after allogeneic SCT. 16 In all of them, galactomannan antigenemia fell within 6 weeks of infusion to the normal range whereas it persisted in all 13 patients who did not receive adoptive immunotherapy; 9 out of the 10 patients who received anti-Aspergillus T cells survived. However, the donor-derived pathogen-specific T cells that were characterized as T H 1 cells were generated by limiting dilution, which needed a minimum of 25 days.…”

“…In contrast to T H 2 reactivity that is associated with susceptibility to invasive mycoses, T H 1 cells play a crucial role in the control of Aspergillus infection, but the factors that determine the differential activation of T H 1 or T H 2 cells are not fully understood. 20,21 In a pilot study, Perruccio et al 16 transferred between 1 Â 10 5 and 1 Â 10 6 anti-Aspergillus T H 1 cells per kg body weight to the transplant recipient between days þ 17 and þ 37 after SCT. The assessment of postimmunotherapy T-cell responses revealed stable frequencies of anti-Aspergillus T cells for up to 36 weeks after SCT, which were associated with control of Aspergillus antigenemia.…”

The changing role of stem cell transplantation in childhood

“…25 Indeed, patients given a T-cell-depleted allograft have offered a unique opportunity to develop strategies of adoptive immune cell therapy, which are expected to play a major role in the future transplant approaches for optimizing the final outcome of subjects given an allograft of HSC. [26][27][28][29] A new actor in the scenario of transplantation: MSCs MSCs are multipotent BM cells able to differentiate in vitro and in vivo into different tissues of mesenchymal origin. 30 Recent studies indicate that MSCs have immunosuppressive properties.…”