Site of initiation of the plasma cell reaction in the rabbit lymph node. Ultrastructural evidence for two distinct antibody forming cell precursors.

Two times sublethal total body-X-irradiation with weekly local thymus irradiation established a T-cell deprived experimental model in rabbits. Humoral immunity reactions in draining lymph nodes have been analyzed histologically and at the submicroscopical level after challenge with Salmonella Java vaccine, horse spleen ferritin, horse-gamma-globulin, a chemical sensitizer oxazolone (2 phenyl-4-ethoxymethylene-5-oxazolone) and after skin allografting respectively. The time sequence studies in these animals with an 'isolated B-cell system' are compared with similar experiments in normal non-irradiated rabbits. The site of initiation of the thymus-independent and thymus-dependent plasma cell response is established in the lymph node. The (ultra)structural features of the antibody forming (-B-)cell precursors, the marginal zone cells, are described and discussed. The differentiating off-spring of two (sub)microscopically recognizable plasma cell lines is presented.     

The graft-versus-host reaction in the rabbit spleen. Ultrastructural evidence for two differentiated T-cell lines

Lethally irradiated (900 rads), bone-marrow-protected rabbits were given allogeneic thymocytes intravenously. Autoradiography by means of local splenic infusion of (H3) thymidine revealed progeny of two differentiated T-cell lines. Electron microscopy confirmed these observations in detail. An analogy with cellular immunity reactions in an "isolated T-cell system", performed in draining lymph nodes after a variety of antigenic stimuli is presented. The functional properties of these T-blasts and their lymphoid descendants are discussed.     

Effect of the low molecular weight thymus factor on T-cells in human blood]

Lowmolecular factor of polypeptide nature (thymarin) was extracted from calf thymus. This factor differed by physical and chemical characteristics from thymosin. The percentage content of "active" T-lymphocytes increased under the effect of thymarin in the cultures of lymphoid cells obtained from healthy individuals. The total T-cell count remained unchanged. Thymarin favoured increase of the total T-lymphocyte and "active" T-lymphocyte count in the cultures of cells from patients with chronic inflammatory processes. Cellular immunity reactions were restored and the course of the main disease improved under the effect of parenteral administration of thymarin. It is supposed that T-immunity system incompetence was associated with the inadequate production of the thymus factor capable of restoring the activity of the thymus-dependent lymphocyte population.     

Immunologic properties of protein-lipopolysaccharide complexes. IV. Circumventing suppression in immunologically tolerant animals

Mice which have been rendered immunologically tolerant to lysozyme by neonatal exposure to this antigen contain suppressor cells as demonstrated by cellular cotransfer experiments. Nevertheless these mice can be induced to respond to lysozyme by immunization with a lysozyme-lipopolysaccharide (LPS) complex. Such immunization results in a primary antibody response but not in induction of immunological memory. However, B-cell priming can be demonstrated in these animals. Similar induction of B-cell priming in normal animals is shown to be T-cell dependent, thus confirming earlier evidence that lysozyme-LPS is a thymus-dependent reagent. The possible mechanisms which underlie these findings are discussed.     

Role of the T-cell system in glomerulonephritis induced in rats by human serum albumin (HSA)

The primary role of the T-cell system in immune-complex glomerulonephritis induced by intravenous weekly injections of human serum albumin (HSA) in rats has been demonstrated. The development of histological, ultrastructural and immunological glomerular alterations which are clearly recognizable in intact animals was prevented by neonatal thymectomy. In vitro tests of cellular immunity (LIF and PHA responsiveness) revealed a close relationship between the involvement of functioning T-cell subpopulations (at least T-helper) and the development of the classic glomerulonephritic pattern. In other words HSA antigen recognition by T lymphocytes, their cooperation with B lymphocytes, and the activation of the latter with related antibody response represent the immunological sequence which leads to the formation of the soluble circulating immune-complexes responsible for the glomerular injury. Our findings suggest that the same immunological sequence can represent the pathogenetic basis for many forms of glomerulonephritis in which T-dependent antigen stimulation is demonstrable. Our data are also discussed in the light of results obtained by others in immuneglomerulonephritis induced in nude athymic mice.     

Freedom of information legislation and medical records.

In a previously healthy 13-year-old girl with disseminated blastomycosis, immunodeficiency was considered because of lymphopenia and the slow response of her lung disease to therapy with amphotericin B. Cellular immunity was found to be profoundly impaired, with absent delayed cutaneous hypersensitivity to several common antigens, a decreased count of thymus-dependent lymphocytes in the peripheral blood and a greatly diminished in-vitro proliferative response of lymphocytes to phytohemagglutinin (PHA). Humoral immunity was intact. Two additional types of therapy were assessed: subcutaneous injection of transfer factor was associated with an unsustained increase in lymphocyte counts and a positive cutaneous response to PHA but no clinical change; parenteral alimentation to ensure an adequate energy intake was associated with rapid clinical improvement, the development of delayed hypersensitivity to four additional antigens, and the return of lymphocyte counts and proliferative response to normal. These findings suggest that increased energy intake rather than transfer factor therapy was responsible for the child''s recovery, and they emphasize the importance of adequate nutrition in the maintenance of intact cellular immunity.     

Experimental malaria in the CBA/N mouse.

CBA/N mice carry an X-linked, recessive gene, which results in the absence of a B cell subset, and is expressed primarily as an inability to respond to a certain class of thymus-independent antigens. We have examined the responses of these mice to the malaria parasite Plasmodium yoelii and found that primary infections induced by this parasite are more severe and last longer in mice with X-linked defect than in normal controls. The decreased resistance of the defective mice is associated with a striking deficiency in their IgM antibody response. After recovery from a primary infection, defective mice resist reinfection with the homologous parasite as well as normal mice. Although as resistant as normal controls, B cells from defective mice transfer considerably less immunity to naive recipients than B cells from normal animals. Hence, two modes of thymus-dependent protective immunity may contribute to the host response to P. yoelii. Control of an acute primary infection appears to involve a thymus-dependent antibody response that CBA/N mice are deficient in. Resistance to reinfection may be mediated primarily by a different mechanism.     

Role of cyclic AMP on differentiation of T- and B-lymphocytes during the immune induction.

Spleen cell cultures from genetically thymus-deficient nude mice were restored with a T-cell replacing factor obtained from normal spleen cells of Balb/c-Ig^b mice stimulated with concanavalin A. Treatment of these cultures with an inhibitory dose of cyclic AMP did not result in reduction of the number of specific antibody-forming cells after stimulation by antigen, whereas the same treatment led to inhibition in cultures restored with normal hydrocortisone-resistant thymus lymphocytes. Further experiments lead to the conclusion that the early effect of cAMP on the immune induction seen in vitro reflects inhibition of the production or secretion of a T-cell factor which is a prerequisite for triggering B-cells with a thymus-dependent antigen.     

Studies on recovery mechanism from rinderpest virus infection in rabbits. I. Effect of anti-thymocyte serum and thymectomy.

The role of cell-mediated immunity in recovery from rinderpest virus infection in rabbits was investigated by application of immunosuppressive procedures, i.e., treatment with anti-thymocyte serum and combined treatment with thymectomy and anti-thymocyte serum, both of which were confirmed to depress significantly cell-mediated immunity in rabbits. The immunosuppressed animals recovered in almost the normal fashion in terms of clinical signs, of virus clearance from the blood and lymphoid tissues and of repair of the lesions. It was suggested that the thymus-dependent cell-mediated immunity may not be essential in recovery from rinderpest virus infection. Possibility of participation of other recovery mechanisms was discussed.     

E-rosette receptors induced by phytohemagglutinin on human K cells expressing T-cell surface antigens.

Killer cells (K cells) enriched from human blood mononuclear cells which mediate antibody-dependent cellular cytotoxicity (ADCC) were examined for surface markers. Sixty-seven percent of the E-rosette-negative, sIg-negative cells reacted with anti-T cell serum (AMT) previously shown to react with immunochemically defined T-cell antigens. Phytohemagglutinin induced 25% of K cells to express an E-rosette receptor. When these induced cells were isolated, greater than 98% reacted with AMT and 17% expressed the Fc receptor for IgG. Furthermore, they retained their functional capacity in ADCC. These findings demonstrate that an E-rosette receptor can be induced on human K cells. The data suggest the K-cell fraction included a population of thymus-dependent lymphocytes which can function as effector cells in ADCC.     

T-cell-receptor gene therapy

T cells are tightly controlled cellular machines that monitor changes in epitope presentation. Although T-cell function is regulated by means of numerous interactions with other cell types and soluble factors, the T-cell receptor (TCR) is the only structure on the T-cell surface that defines its antigen-recognition potential. Consequently, the transfer of T-cell receptors into recipient cells can be used as a strategy for the passive transfer of T-cell immunity. In this review, I discuss the pros and cons of TCR gene transfer as a strategy to induce defined virus- and tumour-specific T-cell immunity.     

Studies of the mechanisms for the induction of in vivo tumor immunity. I. Induction of primary and secondary cell-mediated cytotoxic responses by adoptive transfer of lymphocytes.

Cell-mediated immunity to FBL-3, a syngeneic Friend virus-induced leukemia in C57BL/6 mice, could be adoptively transferred. Characteristic primary and secondary cytotoxic responses could be induced by adoptive transfer of normal and presensitized lymphocytes, respectively. In vivo tumor immunity could also be produced by adoptive transfer of presensitized lymphocytes. Both the primary and secondary cell-mediated cytotoxic reactions were T-cell dependent. The specificity of these reactions was primarily directed against F (Friend) type-specific antigen and FMR (Friend, Moloney, Rauscher) common antigen. The cytotoxic responses produced by adoptive transfer experiments gave better correlation to in vivo tumor immunity than those generated by in vitro mixed lymphocyte tumor cell culture reactions.     

Production of a T-Cell Clone Which Reacts with Membrane Proteins of Acholeplasma laidlawii

The role of cellular immunity in mycoplasma infection is not completely understood. In this study, we established mycoplasma-specific T-cell clones to evaluate cellular immunity in mycoplasma infection. We developed a T-cell clone (G-10) which was stimulated with Acholeplasma laidlawii. The T-cell clone G-10, CD4⁺ and T-cell receptor (TCR) αβ⁺ recognized the 42- and 65-kilodalton (kDa) membrane proteins of A. laidlawii and responded to A. hippikon. Hence, the application of mycoplasma-specific T cells such as G-10 in animal models may allow the assessment of cellular immune response to mycoplasma infection.     

Effect of highly purified thymus factor on the cellular and humoral indices of immunity in thymectomized mice]

Effect of homogeneous polypeptide thymus factor of mol weight about 5000 (thymarin-III) on cellular and humoral immune responses of thymectomized adult CBA mice was studied. Thymectomy proved to greatly decrease the number of T-cells in the spleen. Accordingly, the capability of these mice to produce both IgM and IgG antibody-forming cells in response to the thymus-dependent antigen (sheep red blood cells) was significantly depressed. Subcutaneous injections of thymarin-III (1 microgram per g of body weight) for 7 days completely restored the T-cell spleen population and normalized the animals' immune response.     

Effect(s) of lipopolysaccharide on lectin-induced T-cell activation

The present study focuses on the effect of lipopolysaccharide (LPS) on the cellular events leading to T-cell activation by concanavalin A (Con A). Interleukin 2 (Il-2) production is much reduced in Con A-stimulated cultures of spleen cells derived from LPS-treated mice. This depressed Il-2 synthesis is not related to the eventual activity of LPS-activated suppressive B cells. Rather, it reflects an ineffective collaboration between adherent cells and T lymphocytes. The low level of Il-2 produced by LPS-sensitized spleen cells is sufficient for lectin-induced T-cell proliferation. Moreover, acquisition of responsiveness to Il-2 is unaltered by LPS. No strict correlation was found between the deficiency in Il-2 production and the inability of LPS-sensitized spleen cells to generate a thymus-dependent response. Less time (5 hr) is needed for LPS to exert its inhibitory effect on an anti-sheep red blood cell response than on Il-2 synthesis (at least 24 hr). Results are discussed in terms of cellular interactions implicated in a polyclonal T-cell response and with regard to the contribution of Il-2 to the LPS-induced immune unresponsiveness.     

Enhanced induction of intestinal cellular immunity by oral priming with enteric adenovirus 41 vectors

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by the rapid onset of intestinal T-cell depletion that initiates the progression to AIDS. The induction of protective immunity in the intestinal mucosa therefore represents a potentially desirable feature of a preventive AIDS vaccine. In this study, we have evaluated the ability of an enteric adenovirus, recombinant adenovirus 41 (rAd41), to elicit intestinal and systemic immune responses by different immunization routes, alone or in combination with rAd5. rAd41 expressing HIV envelope (Env) protein induced cellular immune responses comparable to those of rAd5-based vectors after either a single intramuscular injection or a DNA prime/rAd boost. Oral priming with rAd41-Env followed by intramuscular boosting with rAd5-Env stimulated a more potent CD8⁺ T-cell response in the small intestine than the other immunization regimens. Furthermore, the direct injection of rAd41-Env into ileum together with intramuscular rAd5-Env boosting increased Env-specific cellular immunity markedly in mucosal as well as systemic compartments. These data demonstrate that heterologous rAd41 oral or ileal priming with rAd5 intramuscular boosting elicits enhanced intestinal mucosal cellular immunity and that oral or ileal vector delivery for primary immunization facilitates the generation of mucosal immunity.     

Host defense in cryptococcosis. II. Cryptococcosis in the nude mouse.

In the homozygous state, mice carrying the “nude” (nu) gene are hairless (nude), lack a thymus and have profound deficiency of cell-mediated immunity. Cryptococcosis was studied in BALB/c and Swiss mice, each strain carrying the nu gene. The purpose was to determine the interactions of the nu gene and mouse strain in terms of susceptibility to Cryptococcosis. Mice of both strains could be sensitized to produce delayed-type hypersensitivity reactions to cryptococcal extract in the heterozygous nu/X state, but not in the nu/nu state. Nu/X Swiss mice were more resistant than nu/X BALB/c mice to infection with a highly virulent strain (B) of Cryptococcus neoformans. However, nu/nu BALB/c and nu/nu Swiss mice were both highly susceptible to the same microorganism. Challenge with another cryptococcal strain (A) of much lower virulence for nu/X mice killed 100% of BALB/c and Swiss nu/nu mice. These studies indicate that thymus-dependent immune functions are critical determinants of host resistance to murine Cryptococcosis.     

CD8+ T-cell priming regulated by cytokines of the innate immune system

Host protection against a variety of pathogens and tumours requires the efficient induction of CD8(+) T-cell responses. Yet, it has proven difficult to develop vaccines that effectively stimulate this type of cellular immunity. One well-defined obstacle is antigen accessibility to the MHC class I processing pathway. However, cytokines that are produced by cells of the innate immune system also have a key role in CD8(+) T-cell responses, by enhancing 'cross-presentation' and/or inducing CD8(+) T-cell priming and differentiation. Here, we discuss how innate cytokine responses regulate CD8(+) T-cell immunity, and argue that a greater understanding of these processes will be essential for effective tailoring of vaccine-induced cellular immune responses.     

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.     

Cytochemistry of normal and leukaemic lymphocytes: a review.

Findings with six cytochemical reactions demonstrable in normal and leukaemic lymphocytes were reviewed. The two methods which are presently of greater diagnostic value are the acid phosphatase (AP) and alpha-naphthyl acetate esterase (ANAE) reactions. AP has a definitive role in the diagnosis of acute and chronic T-cell leukaemias, where a strong positive reaction helps to distinguish them from most B-cell lymphoproliferative disorders. New findings concerning the ultrastructural localization of this enzyme are presented. ANAE is of value in distinguishing T-lymphocytes (positive localized reaction) from B lymphocytes (negative reaction) and the T micron from the T gamma subpopulation of T-lymphocytes, a positive reaction demonstrable only in the T micron cells. Other reactions reviewed were PAS, beta-glucoronidase, hexosaminidase and alkaline phosphatase.