G.Gy. Petrányi

Increased killer cell activity in aged humans.

Natural cell-mediated cytotoxicity (NCMC) against a cell line (K-562) and antibody-dependent cellular cytotoxicity (ADCC) against the same target and against chicken red blood cells were investigated in two age groups (20--45 and 70--98 years old). Proliferative response to PHA and to allogenic cells as well as some subpopulation determinations were also carried out only lymphocytes of the same subjects. In contrast to the significantly decreased proliferative responses, NCMC showed a moderate, and the two ADCC values a highly significant increase in the group of aged subjects. These increased values showed some similarities with the quantitative changes within the T-lymphocyte subpopulations. The incidence of serum samples of NCMC inhibitory activity was only moderately increased in the group of aged subjects as compared to that of the young individuals. On the basis of these results, we concluded that the immune system of healthy aged subjects seems altered or inbalanced rather than depressed to that of the young individuals.

Levamisole-induced neutropenia and agranulocytosis: association with HLA B27 leukocyte agglutinating and lymphocytotoxic antibodies.

Among 37 patients treated with levamisole for rheumatoid arthritis (n = 19), for Reiters disease (n = 4) and for chronic articular brucellosis (n = 14) followed up during 6-12 months, 3 developed agranulocytosis and 3 severe neutropenia. Serum samples drawn before and during treatment were tested for leukocyte agglutinating and lymphocytotoxic antibodies. Leukocyte agglutinating antibodies were induced in 8 patients, in 5 of them in association with agranulocytosis or neutropenia. In 1 patient with agranulocytosis and in another one with neutropenia lymphocytotoxic antibodies were also induced. Two agranulocytotic and one neutropenic patient possessed HLA B27 antigen. In altogether 11 HLA B27 carriers the number of circulating neutrophils were significantly reduced during levamisole treatment when compared with those of patients lacking HLA B27 antigen.

Graft-versus-Host Disease in Bone Marrow Transplantation: Experimental, Laboratory, and Clinical Contributions of the Last Few Years

Graft-versus-host disease (GVHD) is a major and often lethal complication of bone marrow transplantation. Research of the past few years has greatly expanded our understanding of the disease and enriched the arsenal of preventive and therapeutic procedures. The present review attempts to give a survey of experimental and clinical GVHD, updating essential knowledge with the latest information until July 1993. The covered topics include the complex immune pathomechanism of acute and chronic GVHD in murine models, the pathogenic role of major, minor, and other antigenic disparities, laboratory markers predicting GVHD, factors influencing appearance and course of the disease, the relationship between GVHD and the graft-versus-leukemia effect, and novel experimental and clinically tested preventive and therapeutic modalities. Finally, the authors set forth their perspective on the most relevant questions in GVHD-related research.

Effect of Histamine Receptor Blocking on Human Antibody‐dependent Cell‐mediated Cytotoxicity

The effect of H1 and H2 receptor‐blocking agents on antibody‐dependent cell‐mediated cytotoxicity (ADCC) was studied. The H1 receptor blocker clemastinum and the H2 receptor blocker cimetidine dose‐dependently inhibited the antibody‐dependent cytotoxic activity of normal human peripheral blood mononuclear cells on chicken erythrocytes. The inhibition cannot be explained either by a direct toxic effect on effector cells or by blocking of Fc receptors. The possible involvement of histamine receptor‐bearing effector cells in human ADCC is suggested.

Regulatory function of cell surface molecules CD2-, LFA- and β2-microglobulin in natural killer cell activity

The functional importance of various cell membrane bound molecules was studied and compared in the NK cytotoxicity and CTL activity. LFA-1 and CD2 participate in both killing functions, while CD3 and CD8/CD4 as well as MHC class I molecules are involved only in CTL activity. Nevertheless CD2- and beta 2-microglobulin are representatives of the NK function. It was demonstrated that CD2-, LFA-1 and beta 2-microglobulin molecules have an additive and complementary function in the killing mechanism. The upregulation of alpha- and gamma-interferons on NK function seems not to be a consequence of the enhanced expression of these molecules on the cell surface induced by IF at the same time.

HLA and T-lymphocyte function in old age

The role of the major histocompatibility complex in the genetic control of reactivity of peripheral blood mononuclear cells (T lymphocytes) to lectins and allogeneic cells as a function of age was investigated. In randomly selected aged subjects the frequencies of HLA-A, B, and some C locus alleles did not differ significantly from those in the control group. However, some tendencies of haplotype frequency differences between young and aged subjects were found. Significant associations of impaired or preserved T-lymphocyte function could be detected in connection with some HLA-A (A3, A11) antigens only. The tendency of some phenotypic HLA-A and B or C and B antigen associations to be in correlation with impaired or preserved T-lymphocyte reactivity in old age seemed to be independent of their age-related frequency differences. In family studies of a partially inbred Hungarian population, differences were found in the rate of diminution of allogeneic reactivity in groups sharing different HLA haplotypes. Based on statistical analysis of these data, a genetic factor segregating with the MHC and taking part in the regulation of the age-dependent decline of T-lymphocyte reactivity can be postulated.

Analysis of the age-related refractoriness of T-lymphocyte reactivity in humans

Aged individuals could be divided into two groups according to their T-lymphocyte transformation values. The relationship between the PHA (phytohemagglutinin) stimulation indices and spontaneous thymidine incorporation; the PHA dose-response type distribution and the relative number of resting T lymphocytes was similar to the control group in aged subjects of seemingly intact T lymphocyte transformation values. However, their B cell compartment was found to be reduced. On the other hand, the ratio between the stimulation indices and spontaneous thymidine incorporation values of aged subjects of impaired T lymphocyte reactivity deviated from that of the control group. This group had an increased frequency of subjects giving maximal transformation values at relatively high PHA doses (hyposensitives) at the expense of normosensitives and showed reduced numbers of resting T cells, but normal B cell compartment. These results suggest that immunodeficiencies developing with age can possibly be of individually different types.

Lymphocyte subpopulation changes by aging

Peripheral blood lymphocyte suspensions of healthy young and aged subjects were tested for the percentage of (1) E-rosetting cells by three different modifications of the rosette technique; (2) alpha-naphthylacetate esterase positive cells of different staining patterns; (3) IgG-Fc receptor positive cells; (4) C3 receptor positive cells; (5) labile and stable bound surface immunoglobulin positive cells; and (6) cells bearing different classes of immunoglobulins on their surface or intracytoplasmically. Age dependent changes were registered both within the T-cell and the B-cell subpopulations, some of which may be due to in vivo activation of lymphocytes. Attention is called to some technical aspects of lymphocyte subpopulation determinations and to the significance of quantitative changes in the proportions of lymphocyte subpopulations in respect to the age dependent functional changes of lymphocytes.

Progress in Immunology Vol. VIII

Interleukin-4 present during priming causes naive T cells from T cell receptor transgenic mice to develop into cells capable of producing IL-4 upon secondary challenge. It also suppresses the capacity of such cells to produce IL-2 and interferon gamma (IFNy). This effect is not mediated through the action of 1L-1 O. Priming for IL-4 production is opposed by IFNy, but only at sub-optimal concentrations of IL-4. Different types of antigen-presenting cells display different potencies for priming but all require IL-4 to cause the development of IL-4-producing cells. Administration of anti-IL-4 at the time of in vivo priming with keyhole limpet hemocyanin (KLH) diminishes development of T cells that produce IL-4 in response to in vitro challenge with KLH for up to 75 days after immunization and diminishes the capacity of T cells to produce IL-4 after secondary in vivo challenge. By contrast, anti-IL4 administered at the time of secondary challenge has no effect on subsequent production of IL4. Used acutely, in vitro, IL-4 blocks accessory cell-dependent, receptor mediated IL-2 and IFNy production. Analysis of mechanism indicates that the activated T cell is the target of IL-4 activity and that inhibition is not due to blockade of the CD28 B7 axis or its signalling pathway. It is concluded that IL-4 is a major physiologic regulator of the differentiation of C D4+ T cells into Iymphokine-producing cells. The determination of the source and the clarification of the regulation of such acute IL-4 production are key to understanding the factors that determine whether immune responses will be dominated by IL-4 or by IFNy-

The different effect of alpha and gamma interferons and interleukin 2 on the expression of CD2, CD3, CD4 and CD8 antigens in comparison to histocompatibility antigens of human lymphocytes

The effects of alpha- and gamma-interferons (IFN-alpha, -gamma) and of interleukin 2 (IL-2) on the expression of certain differentiation antigens were compared with those of major histocompatibility antigens on human lymphocytes. IFN-gamma and IFN-alpha in high doses significantly increased the expression of T11 (CD2) differentiation antigen, but did not affect the expression of T4 (CD4), T8 (CD8), T3 (CD3) and Leu-7 antigens (HNK-1). Both natural and recombinant IFN-alpha and -beta apparently increased the expression of HLA-ABC antigens and of beta-2 microglobulin (beta 2m) after 16 h incubation. The amount of HLA-DR antigen, however, doubled in a few hours following IFN-gamma treatment. IL-2 affected the expression of CD2 and CD8 antigens only marginally, but did not affect that of CD3 and Leu-7; however, it strongly enhanced the expression of HLA-ABC, HLA-DR, and beta 2m antigens.