Ontogeny of lymphatic structures in the pig omentum

Summary The development of lymphoid populations in the omentum majus during the prenatal and postnatal life of the pig was studied. T lymphocytes, monocytes and mast cells were first found on the 40th day of gestation. B lymphocytes appeared on the 72nd day of gestation when the first macrophage aggregates were formed. Macrophages appeared to be the prerequisite for the formation of dense lymphatic areas (DLA's). At later stages T cells were observed only in the omentum of germfree pigs. DLA's of conventional pig omentum are filled exclusively with B cells.     

再循环T细胞昼夜节律现象的数学模型

根据人体和小鼠免疫细胞昼夜节律实验结果,提出皮质类激素对淋巴结和脾脏中T细胞再循环产生不同作用的假设,建立了皮质类激素作用下的T细胞在不同外周淋巴器官（淋巴结、脾脏）与血液之间再循环过程的数学模型,讨论了皮质类激素作用的强度、有关参量的取值范围和模型对参数的依赖性. 模型能够解释参与再循环的T细胞在淋巴结、脾脏与血液中的稳定振荡行为,得到的数值模拟结果与免疫系统生物节律实验结果一致.     

T lymphocyte development and maturation in horses

Monoclonal antibodies specific for equine T lymphocyte subpopulations were produced and procedures for the continuous culture of equine lymphocytes were developed. These reagents and procedures were used to analyse the appearance, maturation and functions of T lymphocytes in normal horses and in T lymphocyte deficient horses with severe combined immunodeficiency (SCID). T lymphocytes appeared as early as the 75th day of fetal development and were normally distributed prior to birth of normal foals. Analysis of thymic T lymphocyte differentiation in SCID foals revealed the presence of both prothymocytes and mature thymocytes, but a virtual absence of cortical thymocytes. The data obtained support the hypothesis that two distinct pathways of T lymphocyte differentiation exist within the thymus. Although the gene defect in foals with SCID blocks the production of mature B and T lymphocytes, such foals do possess large granular lymphocytes which are cytotoxic following induction with interleukin 2. This suggests that lymphoid cells with natural killer cell activity are spared by the gene defect resulting in SCID in horses.     

Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxin-sufficient B lymphocytes drive the formation of mature isolated lymphoid follicles

Isolated lymphoid follicles (ILFs) are recently appreciated members of the mucosal immune system. The architecture, composition, and inducible nature of these structures indicates that these structures are tertiary lymphoid structures. The process leading to the formation of tertiary lymphoid structures, lymphoid neogenesis, has been observed in a number of inflammatory and autoimmune conditions. Given this association, there is considerable interest in identifying the factors promoting lymphoid neogenesis, and understanding the steps in this process. Using murine ILF formation as a model, we have examined the roles of different cellular sources of lymphotoxin (LT) and the adaptive immune response in lymphoid neogenesis. In this study, we report that, although other cellular sources of LT may supplant B lymphocytes in the formation of immature ILFs (loosely organized clusters of B lymphocytes), LT-sufficient B lymphocytes are required for the progression of immature ILFs to mature ILFs (organized lymphoid aggregates with a follicle-associated epithelium). ILF formation occurs in the absence of T lymphocytes and Ag-specific B lymphocyte responses, and ILF B lymphocytes express elevated levels of LT in the absence of antigenic stimulation. Consistent with a role for chemokines inducing LT expression in Ag-naive B lymphocytes, and a chemokine-driven positive-feedback loop driving mature ILF formation, mature ILFs express elevated levels of B lymphocyte chemoattractant in the absence of Ag-specific B lymphocyte stimulation. These observations indicate that ILFs contain Ag-naive lymphocytes, and suggest that events occurring within ILFs shape subsequent immune responses mediated by these lymphocytes.     

Functional lymphocytes in the chicken pineal gland

The primary antibody response of lymphoid tissue occupying the pineal gland of 6-wk-old chickens was studied subsequent to injection of the carotid artery with sheep red blood cells (SRBC) or bovine serum albumin (BSA). Injection of SRBC did not produce plaque-forming cells (PFC) among pineal lymphocytes whereas BSA stimulated synthesis of anti-BSA immunoglobulin in pineal lymphoid tissue. A cytotoxic assay using appropriate anti-lymphocyte sera indicated that single-cell suspensions of pineal lymphocytes were composed of 42% B lymphocytes and 51% T lymphocytes. Bursal and thymic lymphocytes labeled with tritiated thymidine migrated into pineal lymphoid tissue when injected into 4- and 5-wk-old naive chicks. These observations indicate that the bursa and thymus make equivalent contributions to the lymphoid mass in the chicken pineal gland. Challenge of pineal-established lymphocytes by antigen introduced via the blood vascular system suggests that soluble antigens--rather than particulate ones--stimulate antibody production in the pineal gland. Collectively, these studies indicate that the pineal gland should be considered as a functional component of the chicken's lymphomyeloid system.     

Lymphoid distribution in the migratory gull Larus ridibundus

We studied the distribution of lymphocytes in the main lymphoid tissues (blood, spleen and thymus) of the gull Larus ridibundus, searching for variations that might depend on the migratory cycle. We also looked for sex- and age-associated differences in lymphoid redistribution. In L. ridibundus, lymphocytes are the most commonly observed leukocyte subpopulation in blood. Moreover, changes in the distribution of lymphocytes in the lymphoid tissue occur, depending on the migratory period. The proportion of these cells in spleen is greater in the post-migratory and pre-migratory periods compared to the non-migratory period. The percentages of circulating lymphocytes are high in the pre-migratory period, but depletion occurs in the post-migratory period. In contrast, the age or the sex of the animals did not confer any major differences on the lymphoid distribution.     

Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue

Background We previously demonstrated that targeting lymphotoxin α (LTα) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune response was initiated at the tumor site. Methods and results In order to directly test this notion, we analyzed the efficacy of tumor targeted LTα in LTα knock-out (LTα^−/−) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTα mediates the induction of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells as demonstrated by in situ TRP-2/K^b tetramer staining. Mechanistically, targeted LTα therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue. Conclusion Thus, our data demonstrate that targeted LTα promotes an accelerated immune response by enabling the priming of T cells at the tumor site.     

Dynamics of T cell activation threshold tuning

T lymphocytes are believed to alter their sensitivity to TCR stimulation by means of a tunable cellular activation threshold. We present two modelling examples which show that the concept of a tunable threshold can be made mechanistically plausible. The tunable threshold is treated as an emergent property of the dynamics of the T cell's signalling machinery. In addition, we discuss how the dynamic properties of activation threshold tuning can be determined experimentally with the aid of these two models. We propose a novel 'avidity selection' mechanism for the initial stages of the immune response, based on the properties of the T cell activation threshold tuning mechanism we propose for the commitment to differentiation. Our main finding is that activation threshold tuning allows T cells to respond to relevant ligands with a detection threshold that is (i) uniform across both the T cell repertoire and the secondary lymphoid tissues, while (ii) retaining tolerance to autostimulation. Our analysis indicates that central tolerance enhances the efficiency of peripheral tolerance, casting new light on the role of negative selection in the thymus.     

Presence of a reversible inhibitor for human lymphoid cell DNA synthesisin the extracts of human peripheral lymphocytes.

An endogenous inhibitor of human lymphocyte DNA synthesis contained in extracts of purified human peripheral lymphocytes is described. It was found that the peripheral lymphocyte extract inhibits the DNA synthesis of phytohemagglutinin (PHA) stimulated human peripheral lymphocytes, lymphocytes in mixed lymphocyte culture, and human lymphoid cells in a long-term culture (PGLC-33H). This extract did not inhibit the DNA synthesis of nonlymphoid cells including HeLa and human embryonic lung. The effects of the inhibitor were reversible and noncytotoxic. Initial characterization showed the inhibitor to be thermolabile, DNase resistant, trypsin sensitive, and stable in a pH range 5.4–8.4. It appears that the inhibitor contained in the purified human peripheral lymphocyte extract is similar to a previously described inhibitor extracted from a human lymphoid cell line (PGLC-33H). Quantitation of the inhibitor in various lymphoid cell populations showed the amount of inhibitor per cell to be higher in resting peripheral lymphocytes than in PHA stimulated peripheral lymphocytes or human lymphoid cells in long-term culture (PGLC-33H). This data suggest that the inhibitor described may play a regulatory role in lymphocyte metabolism.     

Effects of estrogen on the lymphoid regeneration and immune response in irradiated and marrow-reconstituted mice.

Various doses of estriol (E3) were given to mice intraperitoneally, immediately after lethal irradiation and marrow reconstitution. The assessment of the plaque-forming cell (PFC) response to sheep erythrocytes in the spleen and the histological assessment of lymphoid tissues were carried out 30 days later. The effects appeared to be dose-dependent and resulted in a marked suppression of the PFC response. The depletion of lymphocytes was dramatic and dose-dependent in the thymus, and in the thymus-dependent and in the thymus independent areas of the peripheral lymphoid tissues. These results suggest that E3 acts on the differentiation of stem or precursor cells toweard both the populations of T and B lymphocytes. Although E3, given on day 7 after irradiation and marrow reconstitution, suppressed the lymphoid regeneration and PFC response markedly, E3 given on day 14 had no effect. On day 7 the majority of regenerating lymphoid tissues were large pyroninophilic cells and on day 14, small lymphocytes. These results suggest that the precursor or immature lymphocytes are sensitive to E3, while mature lymphocytes are resistant. Lymphoid regeneration and PFC response were retarded in mice irradiated and reconstituted with bone marrow cells from donors pretreated with E3. These results suggest that E3 acts on the stem or precursor cells capable to differentiate in the direction of lymphoid populations and reduce their number in the bone marrow.     

Lymphocyte migration in syngeneic lymph node implants

Lymph nodes implanted subcutaneously to syngeneic recipients were shown to regenerate after mass cell destruction. Regenerated lymphoid tissue has a resemblance to the cortical zone of intact lymph nodes. Microenvironment of regenerated lymphoid tissue provides homing of lymphocytes. However, migration of 51Cr-labelled lymphocytes to implants declined drastically, as compared to lymphocyte migration to intact lymph nodes. Attenuation of proliferative activity and the data of morphological analysis indicate a more prolonged retention of lymphocytes in implanted lymph nodes. The results obtained could be attributable to only partial recovery of sinus and vessel systems regulating the inflow and outflow of lymphocytes in lymph nodes.     

DNA-synthesizing T and non-T cells in chronic lymphocytic leukemia.

In 21 patients with chronic lymphocytic leukemia (CLL) and in 8 hematologically normal persons the number of DNA-synthesizing peripheral blood lymphocytes was investigated by autoradiographic techniques. The lymphocytes were differentiated by EN-rosette tests into T and non-T lymphoid cells. The results show a normal number of proliferating T lymphoid cells and an increased number of proliferating non-T lymphoid cells in clinical stages O-I. Stages III-IV demonstrate a significant increase of the proliferation rate of both T and non-T lymphoid cells. The possible pathogenetic factors and the prognostic value of these results are discussed.     

Changes in the rat lymphoid organs in acute hypoxia

Changes occurring in the rat thymus, spleen, mesenteric lymph nodes have been studied by means of some histological and cytofluorimetrical methods under the effect of an acute hypoxia that imitates the rise to 7,000 m above the sea level for 1 h and to 6,500 m for 6 h. Under the effect of hypoxia, migration of differentiated lymphocytes out of the lymphoid organs is increasing, certain essential shifts in temporal parameters take place in the mitotic cycle of the lymphocytes, contents of nucleic acids in the lymphoid cells change. The phenomena mentioned demonstrate that under the acute hypoxic stress, intensified differentiation processes of the lymphocytes in the thymus, spleen and the lymph node take place and the lymphoid tissue functional activity increases.     

Development of antigenic heterogeneity in the splenic meshwork of severe combined immunodeficient (SCID) mice after reconstitution with T and B lymphocytes

Recently, we produced monoclonal antibodies reacting specifically with the reticular meshwork (RM) of lymphoid tissues, and demonstrated that, in the splenic white pulp of normal mouse, the antigenic heterogeneity of RM was associated with the segregation of the T and B lymphocytes. In the present study, we attempted to visualize further the interaction between splenic RM and T and B lymphocytes transferred into severe combined immunodeficient (SCID) mice. The splenic white pulp of naive SCID mice, containing a few T and B cells, showed little tendency for T-B segregation and antigenic diversity of RM. Transfer of spleen or bone marrow cells from normal mice resulted in complete recovery of lymphocyte populations, showing not only a clear segregation of T and B lymphocytes but also a remarkable antigenic diversity of RM. The same results were obtained following the transfer of spleen or bone marrow cells from the nude mouse. Next, we transferred purified T lymphocytes to one group of SCID mice and B cells to another. In mice given T cells, a few B cells were observed in the white puop; T lymphocytes lodged not only in the inner periarterial lymphatic sheath (PALS) but also in the outer PALS and follicles. In the animals to which B cells were transferred, T cells were few and the homing of B cells occurred only into their proper compartments, such as the outer PALS, follicles and marginal zone, but not in the inner PALS. Thus, B cells can home into their proper compartments of the splenic white pulp independently of T lymphocytes.     

Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis

To test whether accumulation of naive lymphocytes is sufficient to trigger lymphoid development, we generated mice with islet expression of the chemokine TCA4/SLC. This chemokine is specific for naive lymphocytes and mature dendritic cells (DC) which express the CCR7 receptor. Islets initially developed accumulations of T cells with DC, with scattered B cells at the perimeter. These infiltrates consolidated into organized lymphoid tissue, with high endothelial venules and stromal reticulum. Infiltrate lymphocytes showed a naive CD44low CD25- CD69- phenotype, though half were CD62L negative. When backcrossed to RAG-1 knockout, DC were not recruited. Interestingly, islet lymphoid tissue developed in backcrosses to Ikaros knockout mice despite the absence of normal peripheral nodes. Our results indicate that TCA4/SLC can induce the development and organization of lymphoid tissue through diffential recruitment of T and B lymphocytes and secondary effects on stromal cell development.     

The anatomy and topography of the lymphoid formations of the human stomach in postnatal ontogeny]

By means of macro-microscopical methods 80 stomachs from persons of various age have been studied. In the mucous membrane of the human stomach during all age periods of postnatal development the lymphoid tissue is present as diffusely scattered lymphocytes, their microaccumulations and lymphoid noduli. Maximal amount of the lymphoid noduli is observed during the second mature age. The greatest number of the lymphoid noduli per 1 cm2 of the mucous membrane surface is revealed in the area of the lesser curvature and in the pyloric part of the stomach. Most often the lymphoid noduli are situated in the depth of the lumen proper of the mucous membrane, somewhat more seldom--in its more superficial parts, in the muscular lamina and in the submucous tela. The lymphoid noduli with germinative centers are met beginning from the first childhood up to old age. The greatest amount of diffusively scattered lymphocytes is situated near the lymphoid noduli and in the deep layer of the lamina proper of the mucous membrane.     

Evolutionary conservation of tissue-specific lymphocyte-endothelial cell recognition mechanisms involved in lymphocyte homing

Tissue-specific interactions with specialized high endothelial venules (HEV) direct the homing of lymphocytes from the blood into peripheral lymph nodes, mucosal lymphoid organs, and tissue sites of chronic inflammation. These interactions have been demonstrated in all mammalian species examined and thus appear highly conserved. To assess the degree of evolutionary divergence in lymphocyte-HEV recognition mechanisms, we have studied the ability of lymphocytes to interact with HEV across species barriers. By using an in vitro assay of lymphocyte binding to HEV in frozen sections of lymphoid tissues, we confirm that mouse, guinea pig, and human lymphocytes bind to xenogeneic as well as homologous HEV. In addition, we show that mouse and human lymphoid cell lines that bind selectively to either peripheral lymph node or mucosal vessels (Peyer's patches, appendix) in homologous lymphoid tissues exhibit the same organ specificity in binding to xenogeneic HEV. Furthermore, monoclonal antibodies that recognize lymphocyte "homing receptors" and block homologous lymphocyte binding to peripheral lymph node or to mucosal HEV, also inhibit lymphocyte interactions with xenogeneic HEV in a tissue-specific fashion. Similarly, anti-HEV antibodies against organ-specific mouse high endothelial cell "addressins" involved in lymphocyte homing to peripheral lymph node or mucosal lymphoid organs, not only block the adhesion of mouse lymphocytes but also of human lymphocytes to target mouse HEV. The results illustrate a remarkable degree of functional conservation of elements mediating these cell-cell recognition events involved in organ-specific lymphocyte homing.     

Influence of thymectomy on the lymphoid regeneration of hematopoietic bone marrow after sublethal irradiation]

In C57BL mice, bone marrow lymphoid regeneration after a sublethal irradiation is modified by a graft of normal marrow cells. This effect is suppressed in thymectomized mice since a lymphoid peak is observed after a 350 R irradiation; its composition is heterogeneous: small lymphocytes, lymphoblasts and peculier cells named "X cells". The same phenomenon is observed in mice where all the thymocytes and thymus derived and peripheral lymphocytes are destroyed. These results exclude that bone marrow lymphoid regeneration after irradiation is due to a migration of lymphoid cells of thymic origin to the marrow. They could be explained by the effect of a humoral thymic factor on marrow lymphopoiesis.     

Repair of chemical carcinogen-induced damage in DNA of human lymphocytes and lymphoid cell lines--studies of the kinetics of removal of O6-methylguanine and 3-methyladenine

The removal of O6-methylguanine by human lymphoid cells corresponded, with certain assumptions, to a second-order chemical reaction in any given cell. There was a spectrum of proficiency in this respect for a considerable number of cells originating from different individuals and it was found that patients with diseases associated with autoimmunity tended to fall into the less proficient groups. E-B virus-induced lymphoid cell lines, derived from proficient, but not relatively deficient, peripheral blood lymphocytes, always (in 9/9 cases) reflected the level of proficiency of the donor lymphocytes with respect to removal of O6-methylguanine. Thus while proficient lymphocytes always produced proficient cell lines, deficient lymphocytes, in 3/8 cases, gave rise to more proficient cell lines. No evidence was found that groups of individuals exist who lack ability to remove 3-methyladenine from DNA, either from their blood lymphocytes or derived lymphoid cell lines.     

Suppressor cells in homograft tolerant rats.

If sufficient normal syngeneic lymphocytes to effect skin graft rejection are transferred to homograft tolerant rats, a prolonged period elapses before lymphoid cells from the recipient acquire normal levels of GvH responsiveness against tissues of which the donor was previously tolerant (Silvers and Billingham, 1970; Elkins, 1972; Miyamoto and McCullagh, 1974). Although the ability of lymphoid populations of such animals to mount GvH reactions can be demonstrated to reside in donor type cells during the weeks immediately after transfer, reactive cells are ultimately derived from the host itself (Elkins, 1973; Miyamoto and McCullagh, 1974). Not only are lymphoid cells from tolerant rats which have been injected recently with normal lymphocytes poorly responsive in a GvH assay, but they have been observed in some experiments to suppress the GvH activity of normal syngeneic lymphoid cells (Elkins, 1972; Atkins and Ford, 1972). It is not clear whether the cells mediating suppression of the normal lymphocytes were derived from the tolerant host itself or, alternatively, from the normal lymphocytes injected into it to terminate the tolerant state. The present experiments sought to delineate the origin of any suppressor cells within populations of lymphocytes collected from rats in which tolerance had recently been terminated. The indicate that suppression of the normal donor cells within such populations may be exerted by cells derived from the tolerant host.