Publisher Summary Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

Biology of natural killer cells.

Chronic graft-versus-host syndrome in man: A long-term clinicopathologic study of 20 seattle patients

Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and Aspergillosis

SUMMARY Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and aspergillosis.

A series of monoclonal antibodies was used to define three discrete stages of human intrathymic T-cell differentiation The earliest stage was confined to <10% of thymocytes, which were·reactive with both OKT9 and OKT10 Subsequently, approximately 70% of human thymocytes acquired a thymocyte-restricted antigen, OKT6, lost OKT9 antigen, and expressed reactivity with OKT4 and OKT5 These last two monoclonal antibodies were previously shown to define inducer (helper) and cytotoxic/suppressor populations, respectively, in peripheral blood The OKT4+, OKT5+, OKT6+ “common” thymocyte population represents the majority of thymocytes and accounts for more than 70% of thymocytes With further maturation, thymocytes lose OKT6 reactivity, segregate into OKT4+ and OKT5+ subsets, and acquire reactivity with OKT3 (and OKT1) This latter stage corresponds to the more functionally mature subset The possible relationship of acute lymphoblastic leukemia of T-cell lineage to these proposed stages of intrathymic differentiation was determined Analysis of 25 tumor populations showed that 21 could be related to one or another differentiative stage The majority (15/21) were derived from an early thymocyte or prothymocyte subpopulation, 5/25 were derived from a common thymocyte subpopulation, and 1/25 was derived from a mature (OKT3+) subpopulation These data suggest that is it now possible to define stages of T-cell differentiation that can be related to T-cell malignancies in humans

https://www.pnas.org/content/pnas/77/3/1588.full.pdf

Discrete stages of human intrathymic differentiation: Analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage

Severe Aplastic Anemia: A Prospective Study of the Effect of Early Marrow Transplantation on Acute Mortality

Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor.

To determine whether imbalances in immunoregulatory T-cell subsets exist in patients with graft-versus-host disease, we analyzed T cells in three patients with acute and in six patients with chronic graft-versus-host disease after bone-marrow transplantation. The normal human peripheral-blood T-cell compartment is composed of 80 per cent TH2 – and 20 per cent TH2 + T cells, as defined by reactivity with subset-specific heteroantiserums. Human suppressor cells are TH2 +, whereas helper cells are TH2 –. Patients with acute and chronic graft-versus-host disease had abnormalities in these populations, and their T cells frequently bore la-like antigens. Patients with acute disease lacked TH2 + cells, and the reappearance of this subset preceded the cessation of disease activity. Chronic disease, in contrast, was more heterogeneous. Suppressor cells were lacking in two patients but increased in the other four. Two of these four patients had TH2 +,Ia+ T cells, suggesting in vivo activation of suppressor...

Aberrations of suppressor T cells in human graft-versus-host disease.

Two patients with the Wiskott-Aldrich syndrome had complete donor lymphoid and hematopoietic engraftment after successful allogeneic bone-marrow transplantation. One patient had had only a temporary donor T-lymphocyte graft after a previous transplantation, for which he had been prepared with cytarabine and cyclophosphamide; the patient's own T lymphocytes returned six months later. A repeat transplant, for which the patient was prepared with anti-human thymocyte serum, total-body irradiation and procarbazine, resulted in complete donor engraftment. The second patient underwent a successful transplantation after similar preparation, except that procarbazine was omitted. At 11 and five months after transplantation both had normal hematopoiesis and no evidence of graft-versus-host disease. This treatment of the Wiskott-Aldrich syndrome may be a model for the correction of other genetically determined immune and hematologic bone-marrow disorders.

https://www.nejm.org/doi/pdf/10.1056/NEJM197804272981701?listPDF=true

Joel M. Rappeport

Papers

Severe Aplastic Anemia: A Prospective Study of the Effect of Early Marrow Transplantation on Acute Mortality

Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor.

Aberrations of suppressor T cells in human graft-versus-host disease.

Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marrow transplantation

Selection of patients for bone marrow transplantation in severe aplastic anemia.