Characteristics and functions of inflammatory cells isolated from acute graft-versus-host disease target organs after bone marrow transplantation in the rat.
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Animals↗
Biomedical subjects
R Renkonen
Publications and source records attributed to R Renkonen.
Immunobiology of acute graft-versus-host disease.
Acute graft-versus-host disease (aGVHD) remains one of the major obstacles in bone marrow transplantation. The histological changes of aGVHD have been documented thoroughly; much less is known about the inflammatory cell populations causing the reaction. This review focuses on the inflammatory cells isolated from the different target organs during aGVHD.
Animals↗
Cellular infiltrates in the target organs associated with acute graft-versus-host disease.
Acute graft-versus-host disease (AGVHD) has been one of the major obstacles in successful bone marrow transplantation for many years. The histologic manifestations of AGVHD have been well defined but much less is known about the cellular infiltrates in the target organs during AGVHD, the structure of the inflammation is different in different target organs and is not necessarily similar to classical allograft rejection. This review covers, in addition to the histologic approach, the cytologic and functional approaches to the AGVHD associated with inflammatory cells.
Acute Disease↗
Characterization of natural killer cells and their precursors in the murine bone marrow.
We have fractionated murine bone marrow cells according to their density on bovine serum albumin (BSA) gradient and studied (a) the NK activity against YAC-1 targets, (b) the proportion of asialo GM1+ lymphocytes, (c) and the presence of large granular lymphocytes (LGL) in the different fractions (A, B, C, D). The NK activity was found mainly in the C fraction, but the proportion of asialo GM1+ cells was the same in every fraction. No LGLs were found in the bone marrow. Cells from the various fractions were also transplanted into irradiated recipients. Seven days later the highest NK activity was found in the spleens of mice injected with cells from the A + B fractions indicating that the immediate precursors for NK cells reside in the low density fractions of the BSA gradient. Mice transplanted with C or D fractions needed longer time to develop normal NK levels. The treatment of bone marrow cells before transplantation with anti-asialo GM1+ complement did not inhibit the development of NK activity, so it can be concluded that the precursor for NK is asialo GM1-.
Animals↗
Bone marrow transplantation in the rat. B lymphocyte activation in acute graft-versus-host disease.
We have isolated the white cells from the bone marrow, spleen, and blood of a rat recipient of a bone marrow allograft and the inflammatory leukocytes from the recipient skin, lung, gut, and liver (the parenchymal target organs for acute graft-versus-host disease (aGVHD)) and compared the number of immunoglobulin-synthesizing and releasing cells in these cell populations to corresponding compartments of a syngeneic graft recipient. Bone marrow transplantation was associated in the early phase with marked immunoglobulin production in the cells of bone marrow, spleen, and blood of the allograft recipient; as, however, a similar response occurred in the syngeneic graft recipient we conclude that this is related to reconstitution rather than to aGVHD. Later, during aGVHD, the number of immunoglobulin releasing cells decreased significantly in the spleen and bone marrow of the allografted animal. In clear contrast, in the liver--but not in skin, lung, or gut--very few immunoglobulin-releasing cells were observed in the syngeneic graft recipient, whereas in the allograft recipient a very strong and significantly higher immunoglobulin synthesis and release was seen coinciding with the inflammatory episode of aGVHD in the liver.
Animals↗
Bone marrow transplantation in the rat. II. Quantitation of cellular infiltrates in parenchymal target organs in acute graft-versus-host disease.
We have analysed the cytological structure of inflammation in the different parenchymal target organs during acute graft-versus-host disease after bone marrow transplantation in the rat. Inflammation (recovery of increased numbers of white cells) was recorded in the liver, skin, and lungs of the allograft recipient compared with the syngeneic graft recipient from day 5 onwards, accompanied by reduced recovery of inflammatory cells from the gut. The major cytological manifestation of the disorder was an increase in the total number of blast cells, large granular lymphocytes (LGL), and lymphocytes in the liver and skin, and of the number of blast cells and LGL in the lung. At the same time, a depletion of LGL and lymphocytes was recorded in the blood, suggesting migration of these cell components to the site of inflammation.
Agranulocytosis↗
Bone marrow transplantation in the rat. V. Lymphoid cell subclasses in the target organs during acute graft-versus-host disease.
The distribution of white cell subclasses in different lymphoid (bone marrow, spleen, and blood) and parenchymal (liver, skin, lungs, and gut) target organs was studied after bone marrow transplantation in the rat. BN rats were irradiated and transplanted with 60-80 X 10(6) Lew (allogeneic) or BN (syngeneic) bone marrow cells. The recovery of lymphocytes was somewhat elevated in the bone marrow and spleen, slightly decreased in the blood, and markedly higher in the liver and skin in the allograft compared with the syngeneic graft recipient. A mild lymphocytic bronchitis was present in the lungs of the allografted animal, and the gut was hypocellular throughout the observation period. The total recovery of different lymphocyte subclasses; pan T, T helper, T suppressor-killer, class-II-positive cells, and surface-Ig-positive B cells in the different lymphoid organs--i.e., bone marrow, spleen, and blood--was similar in allogeneic compared with syngeneic graft recipients. In the liver and skin, which are the major target organs of acute graft-versus-host disease (aGVHD) in the rat, there was a massive infiltration of different T cell subclasses; high numbers of B cells were also seen in the liver. There was no difference in the T helper/T suppressor-killer ratio in the lymphoid organs or the liver of allograft compared with syngeneic graft recipients; in the skin and lungs the ratio was reduced more in the allograft compared with syngeneic graft recipient, whereas in the gut the situation was the opposite. These observations emphasize regional differences in the structure of inflammation in the different parenchymal target organs of aGVHD in the rat.
Acute Disease↗
Localization and turnover rate of rat renal 'dendritic' cells.
The turnover rate of rat renal dendritic cells was analysed by irradiation and bone marrow transplantation and by visualizing the dendritic cells in frozen sections of renal tissue via double indirect immunofluorescence and peroxidase assays. Interstitial dendritic cells disappear from rat renal tissue shortly after irradiation; after 7 days they can be seen again. However, since the renal proximal tubular cells also simultaneously lose and regain their class II contents, we assume that irradiation has resulted in the disappearance of the Ia antigen, not the dendritic cells proper. After allogeneic bone marrow transplantation, bone marrow-derived dendritic cells appear in renal tissue between days 7 and 10, indicating a relatively fast turnover rate of these cells in vivo.
Animals↗
Turnover of dendritic cells in rat heart.
Taking advantage of the high class II (I-region-associated) antigen content of the tissue dendritic cells and monoclonal antibodies directed to the backbone determinants of the bone marrow donor strain, we have investigated the location and analysed the turnover rate of tissue dendritic cells in rat heart. Low numbers of class II-expressing, factor VIII-negative, non-phagocytic cells with dendritic appearance were observed between the heart muscle fibres. After irradiation with 960 rad, these cells were no longer visible but they reappeared (in lower numbers) on day 20, indicating that they are relatively radioresistant but the antigen expression is radiosensitive. Transplantation of allogeneic bone marrow demonstrated that similar cells appeared from the transplanted bone marrow on day 10, and that these cells populated the heart at a maximum of 20-25 days after transplantation. This indicates a relatively rapid turnover rate, comparable with the turnover rate of dendritic cells in rat kidney and mouse lymphoid tissue.
Animals↗
Bone marrow transplantation in the rat. III. Structure of the liver inflammatory lesion in acute graft-versus-host disease.
The liver is a major parenchymal target organ of acute graft-versus-host disease (aGVHD) after bone marrow transplantation in the rat. The authors have analyzed the nature of cellular infiltrates in the liver using monoclonal antibodies against white cell subsets and investigated the anatomic distribution of the inflammatory cell subsets inside the liver parenchyma. Several types of white cells are present in a normal control liver: In the portal area the T-helper (Th) cells predominate, (surface) immunoglobulin-expressing B cells are present in ample numbers, and most of the phagocytes are Ia-positive. In the central vein area the T-suppressor/killer cells (Tsk) dominate, no B cells are present, and most of the phagocytes are Ia-negative. During aGVHD the number of T cells increases rapidly in the portal area; and after an initial strong increase, the Th/Tsk ratio decreases but remains still above 1. In the central vein area there is also an increase in the number of T cells, compared with that in the syngeneic recipient, but the Th/Tsk ratio rapidly decreases and remains uniformly below 1. During aGVHD the B cells entirely disappear from the portal area, whereas a small but distinct number of mature plasma cells with intracellular immunoglobulin appear in the central vein area. Following irradiation the Ia-positive phagocytic cells entirely disappear from the portal area and decrease distinctly in number in the central vein area. During aGVHD the number of Ia-positive phagocytes increases again in both locations. In the central vein area the positive phagocytes are seen over the background level, and, concomitantly, the Ia-negative phagocytes disappear.
Animals↗
Highly increased natural killer cell number and lytic activity in the murine peripheral blood and lungs after interferon induction in vivo.
We have studied the effect of interferon in vivo (induced by polyinosinic-polycytidylic acid (pIC] on the natural killer (NK) cell lytic activity and on the numbers of large granular lymphocytes (LGL) and target-binding cells (TBC) in different lymphoid compartments. One day after the pIC induction the spleen contained two- to four-fold increased lytic activity without a significant change in percentages of TBC and LGL. In the peripheral blood the lytic activity was 12- to 40-fold higher, and a concomitant clear increase in the number of LGL and TBC was seen. In the lungs the increase in lytic activity was 8- to 16-fold and in the number of LGLs ca. 3-fold. These results demonstrate that not only the lytic activity of the pre-existing NK cells but also the total amount of NK cells is clearly elevated in the body, but this could be seen more significantly in other highly NK-active organs than the spleen.
Animals↗
Immunological monitoring of bone marrow transplant recipients. I. Major leucocyte subclasses in the blood.
In the recipients of an allogeneic HLA-identical sibling transplant the blood leucocytes were reconstituted within 3 to 4 weeks but the level of lymphocytes remained low throughout the observation period of 20 weeks. Of the different lymphoid cell subsets, the large granular lymphocytes (LGL) reconstituted fastest, followed by DR-expressing lymphocytes. The reconstitution was accompanied by a significant lymphoid blastogenesis in the blood. The frequency of OKT4 and OKT8 lymphocytes was initially low; the number of OKT8-positive lymphocytes reached normal levels by the 6-8th week whereas the number of OKT4-positive lymphocytes and, consequently, the OKT4/8 ratio remained low. The responses to the T mitogens, phytohaemmagglutinin and concanavalin A, were strongly suppressed. Only a few significant changes were observed before and during acute graft-versus-host disease (aGVHD): the frequency of LGL, lymphoid blasts and OKT8-expressing lymphocytes was depressed before aGVHD and the frequency of lymphoid blasts remained depressed throughout the episode. We conclude that reproducible changes occur in the leucocyte subset frequencies during reconstitution, but the characteristic changes prior to and during aGVHD are not particularly prominent and hardly of diagnostic use.
Adult↗
The inflammatory mechanisms of allograft rejection.
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Animals↗
Bone marrow transplantation in the rat. I. Histologic correlations and quantitation of cellular infiltrates in acute graft-versus-host disease.
In an attempt to define which cytologic manifestations of inflammation are characteristic of acute graft-versus-host disease (aGVHD), the authors have analyzed hematologic reconstitution in the bone marrow, spleen, and blood of bone marrow transplant recipients and correlated these events to concomitant cytologic changes in the parenchymal target organs. After bone marrow transplantation from Lewis to BN strain, the strongest inflammatory changes were observed in the liver, a "model" parenchymal target organ for aGVHD in this strain combination. The inflammatory episode of the aGVHD in the liver was characterized by an early lymphoid blastogenesis, the presence of large granular lymphocytes (LGLs), lymphocytosis, and some monocytosis, lacking or significantly less prominent in the liver of syngeneic BN to BN recipients. Concomitantly with the infiltration of the liver with LGLs and lymphocytes, these cells were depleted from blood; and with their disappearance from the liver, they appeared in the recipient spleen. Lack of lymphoid blastogenesis in the bone marrow of allograft recipients and similar though less prominent cytologic changes in the syngeneic graft recipients, make it difficult to differentiate aGVHD-associated changes from normal reconstitution in the lymphoid tissue paper; the minimal changes in the blood make this organ the least suitable site for the monitoring of the aGVHD in the rat.
Acute Disease↗
Lymphoid cell subclasses in rejecting renal allograft in the rat.
We have quantitated the frequency of lymphoid cell subsets in rejecting renal allografts and in the spleen of the allograft recipient during drug-unmodified rejection in the rat. The number of inflammatory (white) cells in the graft was approximately similar to the number of white cells responding to the allograft in the recipient spleen. The inflammatory population of the graft consisted of lymphoid cells and mononuclear phagocytes, with increasing numbers of macrophages toward the end of rejection. Analysis of allograft cellular dispersates with monoclonal antibodies directed to the lymphoid cell subsets demonstrated that although the majority of allograft-infiltrating lymphocytes were T cells, a sizable B-cell proliferation and immunoglobulin synthesis was associated with the inflammatory response of rejection. Within the T-cell subset, the T suppressor/killer cells predominated in the graft whereas the predominant lymphoid cell subset responding to the allograft in the recipient spleen was the T helper cell.
Animals↗
Core 2 beta1,6-N-acetylglucosaminyltransferases and alpha1,3-fucosyltransferases regulate the synthesis of O-glycans on selectin ligands on oral cavity carcinoma cells.
Selectin-dependent cell binding has importance in the extravasation of blood-circulating tumor cells and in the generation of metastases. Cell surface glycoproteins decorated with sialylated, fucosylated epitopes, such as sialyl Lewis(x) (sLe(x)), are ligands for selectins. Not only terminal sLe(x) moieties but also proximal core structures contribute to the formation of binding epitopes for selectins. Core 2 beta1,6-N-acetylglucosaminyltransferases (C2GnT) and alpha1,3-fucosyltransferases (alpha1,3-FucT) have been suggested to be the rate-limiting enzymes in the synthesis of selectin ligands. We analyzed oral cavity epithelial carcinoma cell lines and showed their expression of RNA transcripts for C2GnT and alpha1,3-FucT, identified alpha1,3-FucT enzyme activities, and analyzed the cell surface sLe(x) expression levels. Neither the pattern of expressed enzymes nor the alpha1,3-FucT activity directly predicted the binding capacity of E-selectin. However, only the sLe(x)-expressing cell lines were capable of binding to E-selectin, but not to P-selectin, thus putatively promoting the selectin-mediated metastasis. These findings suggest that C2GnT in combination with alpha1,3-Fuc-T contribute to the selectin-mediated metastasis in oral cavity carcinomas.
E-Selectin↗
Bronchoalveolar lavage. Influence of cytologic methods on the cellular picture.
Bronchoalveolar lavage (BAL) was applied to 803 subjects who had various lung diseases or were healthy controls. Combined Millipore (MiPo) filtration of alcohol-fixed cells and cytocentrifugation (CCF) of fresh, air-dried cells was used for the cytologic studies. On the MiPo preparations the proportions (mean +/- SD) of lymphocytes (30.6 +/- 23.7), neutrophils (5.4 +/- 11) and respiratory epithelial cells (2.4 +/- 3.8) were significantly (P less than .001) higher when compared with those on the CCF slides (21.0 +/- 2.3, 3.6 +/- 1.0 and 0.4 +/- 1.5, respectively). The proportions of eosinophils and basophils were nearly the same on the CCF (1.9 +/- 5.3) and MiPo slides (1.6 +/- 6.1). In MiPo filtration the loss and degeneration of cells can be avoided if the cell suspension is fixed prior to filtration. In cellular morphology the two methods complemented each other, and the specificity and sensitivity were the same. In nonparenchymal lung diseases false pathologic cell findings due to bronchial content contamination can be more reliably excluded from MiPo specimens than from CCF ones.
Bronchoalveolar Lavage Fluid↗