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A method for isolation of allograft-infiltrating cells in a functionally viable state is described in this article. The method is based on the use of a spongious tissue into which cells of strain A (e.g., fibroblasts or tumor cells) are grown. The resulting graft is then transplanted to a strain B animal, and the infiltrating cells are released from it by gentle compression. The graft-infiltrating cells are completely recovered, and they may be processed for further experimentation and analysis by employing exclusively physical methods of cell preparation. As an example of future applications, some preliminary results on density- and charge fractionation of the graft-infiltrating cells are also reported.
The identification of mononuclear cells extracted from 12 basal cell carcinomas has been carried out by means of various assays such as the E rosette test, FITC anti-Ig conjugates and peroxidase conjugates viewed at an ultrastructural level. The relative quantities of B and T cells have been determined as well as the morphology of the extracted cells. It was found that the T/B ratio is close to that of a delayed-type reaction to tuberculin, suggesting a possible identical immune mechanism, and also that the morphological appearance of some tissue lymphocytes differs from that of circulating lymphocytes due to the presence of both membrane and cytoplasmic Ig.
The synovial sublining layer of rabbits with synovitis induced by intra-articular injection of cathepsin D digested autologous IgG fragments (Fab2) has been examined under the electron microscope. Twelve or more injections of autologous Fab2 led to chronic synovitis with dense mononuclear cell infiltrates containing lymphocytes, blastic cells, plasma cells and macrophages. In the infiltrates there was evidence that the lymphocytes had been activated prior to transformation into mature plasma cells. Indirect evidence suggests that T lymphocyte activation also occurred in these infiltrates. Cellular contacts between macrophages and lymphocytes or plasma cells as well as between M cells and lymphocytes were demonstrated. These contacts are tentatively interpreted as a feature of ongoing immune processes in the synovium.
Mice that have been injected with Corynebacterium parvum have mononuclear-cell infiltrates in the liver lobules. In such mice a small dose of lipopolysaccharide endotoxin produced a lethal hepatitis, with high serum-transaminase concentrations, glycogen depletion, and hypoglycaemia. It is suggested that lipopolysaccharide triggers the release from the infiltrating mononuclear cells of factors toxic for hepatocytes. Similarly certain parasitic and virus infections and graft-versus-host reactions can sensitise mice to the induction of hepatitis by exposure to small doses of lipopolysaccharide. This model may be applicable to human hepatitis.
In vitro culture of heart biopsy specimens from patients after transplantation in media containing recombinant human interleukin-2 led to the exudation of host mononuclear-cell infiltrates. Cloned T-cell lines were prepared from such infiltrates and studied for donor-specific mixed lymphocyte reaction and cytotoxic T-lymphocyte activity. Although most T-cell clones (greater than 50%) showed donor-specific reactivity, a small but distinct frequency (2% to 10%) of the cloned T-cell lines did not proliferate against donor or third-party stimulator cells. Of interest was our finding that addition of these non-donor-reactive cloned T-cell lines to autologous peripheral blood mononuclear cells markedly suppressed their donor-specific, but not third-party major histocompatibility complex, unrelated proliferative response and prevented the generation of donor, but not third-party, major histocompatibility complex unrelated cytotoxic T-lymphocyte function. The suppression was not secondary to lysis of donor stimulator cells, lysis of autologous donor-specific CD4+ lymphoblasts, or by selective consumption of interleukin-2. The suppression was mediated at the initiation of sensitization (precursor cell level). These suppressor cells expressed CD3, CD8, CD45RO, and the alpha, beta T-cell receptor, but not CD4 or CD56. These cloned T-cell lines will provide unique reagents to study the molecular basis by which these cells exert their regulatory function.
Studies of cultures and cloned T-cell lines from mononuclear cell infiltrates in cardiac biopsy specimens have provided a unique resource to study the cellular basis of human organ allograft rejection. Our laboratory has previously shown that biopsy specimens placed on autologous donor MHC-class-II-specific cloned T-cell lines from previous cardiac biopsies led to the isolation of cloned T-cell lines, which appeared to be functionally "antiidiotypic" in nature. Detailed functional analysis of such CD4+ individual antiidiotype-reactive cloned T-cell lines revealed that although some augmented the proliferative response of autologous idiotype-bearing cloned T-cell lines against donor stimulator cells, others markedly suppressed the proliferative response; thus, although each of these antiidiotype-like reactive cloned T-cell lines appears to specifically react with the same idiotype-bearing donor MHC-class-II-specific cloned T-cell line, they were functionally heterogeneous. Analysis of cytokines secreted by these individual clones showed that the antiidiotype-reactive cloned T-cell lines that suppressed the response of idiotype-bearing cells appear to secrete predominantly interferon gamma, whereas those antiidiotype-reactive cloned T-cell lines that augmented the response do not secrete interferon gamma but secrete interleukin-2, -4, and -6. These preliminary data suggest that differences in the predominant cytokines secreted by these individual antiidiotype-reactive cloned T-cell lines may account for their functional differences.
Cell infiltration is commonly observed in human renal allograft biopsies. This infiltration was investigated using electron microscopy for a more precise assessment of the nature of these cells. More than 3000 cells infiltrating twenty-five renal allograft biopsies were studied. Six cellular types were distinguished and a mean percentage of each type was calculated. Only one-half of these cells were normal or transformed lymphocytes (including small lymphocytes: 22-3 +/- 3-8%, 'intermediary' cells: 22 +/- 3-6%, blast-like cells similar to MLC transformed lymphocytes: 8-1 +/- 2-4%. A relatively high number of plasmocytes (12-4 +/- 2-5%) and a still higher percentage of macrophages (28-5 +/- 4-6%) were found. Granulocytes represented only 2 +/- 0-8%of the cell population. Variations of the mean percentage of these cellular types were studied in various clinical situations.
The behavior of leukemic cell infiltration in the testis or ovary was examined on 99 autopsy cases of various leukemia, which were performed in the Department of Pathology, Tokyo Medical and Dental University, from 1964 to 1975. The incidence of leukemic cell infiltration was 48.5% in the testis and 58.1% in the ovary. The frequency of leukemic cell infiltration in the testis or ovary itself showed no significant increase in recent years, although median survival time became longer by a more aggressive combination chemotherapy. These findings show that the testis and ovary are essentially a preferred site of leukemic cell infiltration. Especially in acute monocytic leukemia, leukemic cell infiltration was revealed in all cases. In addition, short discussions were made on the role of sex hormones in the infiltration, proliferation, and persistence of leukemic cells of each type of leukemia in the testis or ovary.
Immunofluorescent techniques were utilized to identify the types of infiltrating lymphocytes adjacent to human malignant tumors arising from a wide range of anatomic sites. 24 of 29 primary tumors and 5 of 8 metastatic lesions showed varying degrees of lymphocytic infiltration. T cells predominated in the infiltrates in primary tumors (mean 80%, range 50-100%) and this pattern was evident regardless of anatomic site or the presence or absence of metastatic spread. By contrast, B cells predominated at the margins of three of five tumor metastases. Mononuclear cells bearing the Fc receptor were not a prominent component of the infiltrates associated with either primary tumors or metastases, but tumor cell binding of fluoresceinated IgG aggregates was observed in 12 of 29 primary tumors. A significant reduction in peripheral blood T cell numbers occurred in a third of the patients studied. This decrease was not clearly related either to the extent of local tumor T cell infiltration or to the presence of disseminated disease. These preliminary findings provide a descriptive analysis of the local and systemic distributions of immunocompetent cells in cancer.
Cytoenzymatic analysis of cells infiltrating heart transplants in the rat confirms the high participation of monocytes and macrophages. However, when comparing iso and allografts, only slight differences are observed in the lysosomal enzyme specific colorations, whereas a striking difference in these colorations is found between heart infiltrates and peritoneal exsudates from these recipients. This could favour the hypothesis of a local macrophage activating process within the graft but seems more probably due to differences in cell maturation stages.
Functioning mononuclear cells have been harvested from heterotopic rat cardiac allografts during maximal transplant cellular infiltration. T cells, identified by a T cell-specific absorbed rabbit anti-rat brain serum, constituted two-thirds of the total cells recovered. Approximately 20% of the infiltrating cells bear and synthesize surface immunoglobulin. Macrophages, identified by latex ingestion and morphologic and cytochemical techniques, comprise 9% of the graft infiltrate. Donor-specific cytotoxic T lymphocytes are concentrated within the graft. A separate population of Fc receptor-positive recovered cells mediate antibody-dependent LMC (Ab-LMC). Neither effector cell was adherent or phagocytic. These studies have conclusively established that cytotoxic T lymphocytes accumulate within rejecting allografts; however, the enriched presence of cytotoxic T cells within the grafts is not fully dependent upon antigen recognition per se, since Lew animals grafted with both BN and BUF hearts have Lew anti-BN and Lew anti-BUF killer cells in each graft.
Viable, functioning effector cells exerting donor specific cytotoxic properties have been removed, with their surface properties intact, from acutely rejecting cardiac allografts in rats to define immunological events occurring within the grafts themselves. Macrophages comprised 15 to 25% of the cells harvested; lymphocytes comprised about 75%. A few polymorphonuclear leukocytes (approximately 5%) were present consistently. Lymphocytes bearing surface Ig, B cells, made up 35 to 47% of the mononuclear cells collected. The remaining lymphocytes were presumptive T cells. The surfact attributes of the infiltrating cells were compared to those of cells from recipient peripheral blood, spleen and lymph nodes, and to those from isografted controls. Many of the B lymphocytes possessed Fc receptors but were virtually unable to form erythrocyteantibody complement (EAC) rosettes, in contrast to splenocytes which formed approximately 30% EAC rosettes. Specific cytotoxicity against donor alloantigen-bearing cells, as tested in a 51Cr release assay, was shown to be a T cell function by serial fractionation experiments. Peak cytotoxicity of infiltrating T cells occurred early during the rejection process, while that of cells from recipient blood and lymphoid tissues occurred only following complete graft destruction. Antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC) was demonstrated following gentle trypsinization or overnight incubation of the cells. Differing effector cell populations could be distinguished by treatment of anti-Ig and complement; direct donor-specific lymphocyte-mediated cytotoxicity was not disrupted by this treatment, while Ab-LMC was abolished.
Viable infiltrating host leukocytes have been isolated from 10 rejected human renal allografts, removed 1 to 67 months after transplantation. The cell populations have been identified by surface characteristics and their cytotoxic capacities were assessed. A heterogenous population of cells of host origin accumulated in the grafts, including T and B lymphocytes, Fc+ cells, and macrophages. Using a 51Cr release assay, specific cytotoxicity against donor alloantigens was determined. Cytotoxicity of the infiltrating cells was almost invariably greater than cytotoxicity mounted by recipient peripheral blood lymphocytes. Deletion studies confirmed previous work and suggested that T cells were primarily responsible for cytolysis in early acute rejection; non-T cells more often in late chronic rejection. Antibodies eluted from the grafts demonstrated both specific antidonor and nonspecific activity as well as cross-reacting anti-HLA activity. Allograft morphology was examined and cellular and humoral host responses were assessed. These studies emphasize the complexities of immune responses produced by the host against transplanted tissues.
Lymphokine preparations of high potency obtained by in vitro assay were employed in vivo to determine whether they could produce inflammatory responses showing a cellular infiltrate that qualitatively or quantitatively resembled responses of delayed hypersensitivity. Hematogenous cell infiltrates in guinea pig skin were characterized in terms of the number and types of participating cells following intradermal injection of either lymphokines or an antigen (PPD) to which the animals exhibited delayed hypersensitivity. The dose of lymphokine or PPD per skin test site was selected on the basis of comparable ability to enhance vascular permeability. Delayed hypersensitivity responses showed, as expected, a persistent mononuclear cell exudate both in dermis and subcutis, but most notable in the dermis, during the 24 hours following antigen injection. In contrast, the response to lymphokine over the same period was characteristically neutrophilic and principally in the subcutis. There was no pronounced mononuclear cell infiltrate at any time throughout the reaction to lymphokine. It is concluded that preformed lymphokine produces a pattern of increased vascular permeability appropriate to a mediator of delayed hypersensitivity reactions, provided there is sustained secretion of this material. The ability of lymphokine to cause carbon labeling of dermal capillaries is also pertinent to a mediator of delayed hypersensitivity. The absence of significant mononuclear cell accumulation suggests that the in vitro chemotactic activity of lymphokine toward mononuclear cells may be more important for retention of mononuclear cells in the extravascular connective tissue space than for their selective accumulation.
The dermal mononuclear cell infiltrates of psoriatic lesions were characterized by receptors for sheep erythrocytes (T-lymphocytes), C3b receptors (macrophages and B-lymphocytes) and C3d receptors (B-lymphocytes), using hemadsorption to cryostat sections in a closed chamber. T-lymphocytes and macrophages were the predominant inflammatory cells. Very few B-lymphocytes were detected. These findings are discussed in relation to the possible pathogenetic signficance of cellular immunity in psoriasis.
BACKGROUND & AIMS: Emerging evidence supports a crucial role for tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment. Furthermore, research has identified that the triggering receptor expressed on myeloid cells 2 has immunomodulatory functions. The present investigated the potential effect of triggering receptor expressed on myeloid cells 2 expression in tumor-associated macrophages on facilitating immune evasion in colorectal cancer. METHODS: Immunohistochemical analysis of clinical specimens, complemented by extensive data mining from The Cancer Genome Atlas, revealed a significant upregulation of triggering receptor expressed on myeloid cells 2 in colorectal cancer-associated tumor-associated macrophages, with this upregulation exhibiting a correlation with poor patient prognosis. RESULTS: Mechanistically, triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages were found to drive fibroblast activation through transforming growth factor-β signaling, inducing fibroblast-activated protein-positive cancer-associated fibroblasts that secrete collagen I/III to establish dense peritumoral barriers. Spatial profiling revealed that these fibrous structures physically impede CD8+ T-cell infiltration, restricting cytotoxic lymphocytes to stromal compartments. Intriguingly, triggering receptor expressed on myeloid cells 2 deficiency enhanced the secretion of matrix metalloproteinase 13 by macrophages, thereby promoting extracellular matrix degradation and improving T-cell penetration. In vivo, Trem2-knockout mice showed a reduction in tumor growth with enhanced intratumoral CD8+ T-cell infiltration compared with wild-type controls. CONCLUSIONS: Our findings establish triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages as central regulators of stromal remodeling and suggest that therapeutic targeting of the triggering receptor expressed on myeloid cells 2/transforming growth factor-β/fibroblast-activated protein pathway may overcome immune resistance in patients with colorectal cancer.
Whole body X-irradiation (400 rad) of C57BL mice, either before or after i.m. implantation of the syngeneic fibrosarcoma, FS6, influenced both the growth of the tumours and their cellular composition, particularly their macrophage content. Pre-irradiation resulted in slower initial growth of tumours, and a concomitant lack of host-cell infiltration, but when tumours began to grow at a rate parallel to controls infiltration by host cells was demonstrable. Similarly, irradiation of the tumour-bearing host resulted in a temporary cessation of growth, and a decrease in the macrophage content, which did not return to control levels for 2-3 weeks after irradiation. The significance of these results is discussed in relation to the possibility that infiltrating host cells, particularly macrophages, may stimulate the growth of this tumour.