T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Abstract

Aspergillus fumigatus, an opportunistic fungal pathogen, is responsible for multiple airway diseases of an allergic and a nonallergic nature. In a murine model of invasive pulmonary aspergillosis, resistance is associated with a decreased lung inflammatory pathology and the occurrence of an IL-12-dependent Th1-type reactivity that are both impaired by IL-4. In the present study we assess the ability of Aspergillus crude culture filtrate Ags and the recombinant allergen Asp f 2 to induce protective antifungal responses in mice with invasive pulmonary aspergillosis. Similar to what occurred upon nasal exposure to viable A. fumigatus conidia, treatment of immunocompetent mice with Aspergillus crude culture filtrate Ags resulted in the development of local and peripheral protective Th1 memory responses, mediated by Ag-specific CD4+ T cells producing IFN-γ and IL-2 capable of conferring protection upon adoptive transfer to naive recipients. Protective Th1 responses could not be observed in mice deficient of IFN-γ or IL-12 and did not occur in response to Asp f 2, which, on the contrary, elicited high level production of inhibitory IL-4. The results show that Ags of Aspergillus exist with the ability to induce both Th1- and Th2-type reactivity during infection, a finding that suggests a possible mechanism through which potentially protective immune responses are inhibited in mice with the infection. However, the occurrence of Th1-mediated resistance upon vaccination with Aspergillus crude culture filtrate Ags, suggests the existence of fungal Ags useful as a candidate vaccine against invasive pulmonary aspergillosis.

Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

“…5,17 In our experiments, IFN-␥, the Th1-type cytokine, was produced by lymphocytes from normal volunteers when exposed to A. fumigatus only in the presence of DC, and IL-10, a Th2-type cytokine, was not detectable in supernatants from these cultures. In addition, there was a proliferative response to A. fumigatus by normal donor lymphocytes only in the presence of DC.…”

“…In a murine model described recently, 4,5,16,17 Cenci et al noted that mouse strains mounting a Th1 response were resistant to experimental invasive aspergillosis, while those with a predominantly Th2 response succumbed to the infection. In addition, we reported previously that A. fumigatus conidia induced a Th1 response in vitro using peripheral blood mononuclear cells from normal volunteers, 12 suggesting that a Th1 response can also be induced in humans.…”

“…Indeed, animal studies demonstrated that a Th1 response was associated with resistance to induction of experimental Aspergillus infection, 4 and methods stimulating a Th1 response were successful in inducing anti-Aspergillus immunity. 5 We 6 and others 7 have reported that a substantial proportion of blood and marrow transplant recipients have a deficiency in the number of circulating dendritic cells (DC) in the early post-transplant period. To overcome the potential effects of DC deficiency on immune reconstitution post transplant, DC-based vaccines have been used to induce T cell-mediated immunity to tumor early after transplantation.…”

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

“…Animal models suggest that the reconstitution of Aspergillus-specific immune responses after allogeneic SCT is protective against the development of invasive aspergillosis. 13,14 In humans, the approach of adoptively transferring antigen-specific T cells after allogeneic SCT is well established for patients suffering from severe viral disease, such as CMV disease or EBV-associated post transplantation lymphoproliferative disease, 5,15 but there are only few data on patients with invasive fungal infection. In one clinical trial, 10 hematopoietic transplant recipients with evidence of invasive aspergillosis received antiAspergillus adoptive therapy after allogeneic SCT.…”

Generation of Th1 T cell responses directed to a HLA Class II restricted epitope from theAspergillusf16 allergen

“…A total of 104 pentadecapeptides are required to overspan the entire Asp f16 protein. The sequence of the first peptide is MYFKYTAAALAAVLP (aa 1-15), the second peptide overlaps the first by 11-aa, YTAAALAAVLPLCSA (aa [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and the third overlaps the second peptide by 11-aa, ALAAVL PLCSAQTWS (aa 9-23). Immunograde peptides were synthesized and analysed by NMI Technologietransfer GmbH (Reutlingen, Germany).…”