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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1483-1490
TRANSPLANTATION
Defective antifungal T-helper 1 (TH1) immunity in a murine model
of allogeneic T-cell-depleted bone marrow transplantation and its
restoration by treatment with TH2 cytokine antagonists
Antonella Mencacci,
Katia Perruccio,
Angela Bacci,
Elio Cenci,
Roberta Benedetti,
Massimo F. Martelli,
Francesco Bistoni,
Robert Coffman,
Andrea Velardi, and
Luigina Romani
From the Microbiology Section, Department of
Experimental Medicine and Biochemical Sciences, and the Division of
Hematology and Clinical Immunology, Department of Clinical and
Experimental Medicine, University of Perugia, Perugia, Italy.
Patients undergoing full haplotype-mismatched hematopoietic
transplantations may experience severe intractable invasive fungal infections. To verify whether an imbalanced production of T-helper 1 (TH1) and TH2 cytokines may be responsible for susceptibility to fungal
infections, C3H/HeJ (H-2k) recipient
mice were lethally irradiated, received transplantations with
T-cell-depleted allogeneic bone marrow (BM) cells from mice of
H-2d haplotype, and were infected with
Candida albicans. At different time-points after
transplantation, mice were assessed for pattern of TH cytokine
production and susceptibility to infection. The results show that a
long-term, donor-type chimerism was achieved as early as 2 weeks after
BM transplantation (BMT), at the time when high-level production of TH2
cytokines (interleukin-4 [IL-4] and IL-10) and impaired production of
TH1 cytokines (interferon- [IFN-] and IL-12] were observed. At
this time, mice were highly susceptible to both disseminated and
mucosal infections, as indicated by decreased survival, uncontrolled
fungal growth, and failure to develop protective TH1 immunity. However,
a predominant production of TH1 cytokines was observed by week 5 after
BMT, at the time when mice developed donor-type protective TH1
responses and were resistant to infections. Therapeutic ablation of
IL-4 or IL-10 greatly increased resistance to candidiasis. These
results indicate that a dysregulated production of TH cytokines occurs
in mice undergoing T-cell-depleted allogeneic BMT. The transient
predominant production of TH2 cytokines over that of IL-12 impaired the
ability of mice to develop antifungal TH1 resistance, an activity
that could be efficiently restored upon treatment with TH2 cytokine antagonists.
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