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Invasive aspergillosis has become a major cause of infection-related mortality in nonneutropenic patients after allogeneic stem cell transplantation (SCT). To assess the potential role ofAspergillus-specific T-cell responses for the successful control of invasive aspergillosis, lymphoproliferative responses toAspergillus fumigatusantigens were studied in healthy individuals, patients with evidence of invasive aspergillosis, and patients late after allogeneic SCT. In healthy individuals, a positive lymphoproliferative response was documented to cellular extracts of A fumigatus(14 of 16), the 88-kDa dipeptidylpeptidase (4 of 16), and the 90-kDa catalase (8 of 11). A predominant release of interferon γ (IFN-γ) in culture supernatants on stimulation with A fumigatusantigens was demonstrated in 13 of 17 healthy individuals, indicating a TH1 response. In patients with clinical evidence of invasive aspergillosis, a favorable response to antifungal therapy was found to correlate with a higher IFN-γ/interleukin 10 (IL-10) ratio in culture supernatants (n = 7; median ratio, IFN-γ/IL-10 = 1.0; range, 0.09-24.8) compared to 10 patients with progressive or stable disease (median ratio, IFN-γ/IL-10 = 0.1; range, 0.002-2.1; P= .04). Steroid treatment was found to suppressAspergillus-specific lymphoproliferation (P= .037) and release of IFN-γ in culture supernatants (P= .017). In contrast to cytomegalovirus- and tetanus toxoid–specific T-cell responses, Aspergillus-specific T-cell reconstitution late after allogeneic SCT was characterized by low stimulation indices and a low IFN-γ/IL-10 ratio. In addition, phosphoantigen-reactive Vγ9/Vδ2 T-cell clones from healthy individuals were found to produce significant amounts of tumor necrosis factor in response to A fumigatusantigens. In conclusion, these results further support the hypothesis that T cells contribute to the host defense against A fumigatus.

Transplantation of immunocompetent cells present within allogeneic bone marrow has been associated with the elimination of residual host leukemia, both in animal tumor models and in patients receiving marrow transplants for leukemia. This observation has been called the “graft-versus-leukemia effect.” We have attempted to study this phenomenon in vitro by characterizing the cytolytic response of T cells from normal donors after in vitro activation with allogeneic leukemic cells. As expected, most T cells that react against an allogeneic patient's leukemic cells recognize their foreign HLA antigens and lyse the patient's nonleukemic remission lymphoid cells. In addition, we have shown that a small fraction of the T cells recognize and lyse foreign leukemic targets without lysis of nonmalignant remission targets from the same leukemic patient. These T cells have been isolated and characterized as CD3+, CD4+ cells expressing the α/βT cell receptor (TCR). Their lysis appears to reflect specific antigen recognition mediated via the CD3-TCR complex and interactions involving the CD4 receptor. Some of these “leukemic specific” T cell lines, which are restricted by HLA class II molecules, can also lyse occasional nonleukemic cells from certain unrelated donors. This recognition appears to involve crossreactive determinants shared by the leukemic cells and the unrelated allogeneic nonleukemic cells. These specific interactions may represent an in vitro model of the graft-versus-leukemia effect.

Culturing of leukemic blood lymphocytes from a patient with acute T-cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T-cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine- activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.