Biomedical subjects
Publications and source records attributed to G Steinhoff.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
We investigated immunohistochemically the leukocyte infiltrate [CD3, CD4, CD8, CD11a, CD11b, CD14, CD56, VLA-4 and platelet endothelial cell adhesion molecule-1 (PECAM-1)] and the endothelial expression of cell adhesion molecules (PECAM-1, VCAM-1, ICAM-1 and ICAM-2) in 23 renal cell carcinoma tumor tissues. Tumors with a moderate or high density of PECAM-1 positive endothelia showed a stronger infiltration with PECAM-1-positive leukocytes as compared to tumors with a low density of positive endothelia (p<0.0085). Additionally, overall survival of patients who presented with tumors exhibiting a moderate or high density of PECAM-1 endothelia alone or in combination with a PECAM-1-positive infiltrate was extended (median survival: 23.5 months) as compared to patients without these tumor characteristics (median survival: 6.5 months). These results suggest an involvement of PECAM-1 in the process of leukocyte migration and a potential role as a prognostic marker in renal cell carcinoma.
Reactivation of latent rat cytomegalovirus (RCMV) from a lung allograft or from a recipient was studied in RCMV-mismatched combinations (donor [D]-/recipient [R]+, D+/R-, and D+/R+) with latently infected lung grafts and chronically infected rats in an inbred rat model. Nineteen transplants in a major histocompatibility complex different strain combination (Brown-Norway/Lewis) were immunosuppressed daily (cyclosporine, azathioprine, and prednisolone) from day 3 after orthotopic left lung transplantation and killed on days 3, 6, and 21. Control groups consisted of nine chronically RCMV-infected rats with immunosuppression without transplantation and six allografts with immunosuppression without RCMV infection. Reactivation of latent RCMV was tested by immunohistochemical staining with monoclonal antibodies against RCMV-induced antigens and by plaque assays of the virus in the salivary glands. The following results were obtained: (1) All allotransplants developed acute ongoing rejection on days 3 and 6, and the rejection was resolved on day 21 by immunosuppression. (2) Reactivation was observed in allotransplanted groups, but not in the control rats. (3) In the D+/R+ and D-/R+ groups on days 3 and 6, the number of RCMV-related antigen-positive cells increased in the recipient spleen and lymph nodes and in the bronchus-associated lymphoid tissue of the donor lung in the D-/R+ group, but not in the chronically RCMV-infected controls. (4) In the D+/R- group on day 6, RCMV-induced antigen-positive cells were observed in the spleen and lymph nodes of the recipient and also around the vessels in the recipient lung. (5) In the D-/R+ group, vascular endothelial cells or mildly infiltrated mononuclear cell subpopulations around the vessels in the lung allograft showed weakly positive staining against RCMV-related antigens on day 6. (6) After the initial acute rejection on days 3 and 6 was treated by immunosuppressive drugs, reactivated acute RCMV infection became chronic or latent again on day 21. We conclude that RCMV infection could be transferred with latently infected lung allografts by reactivation of latent RCMV. In rats, as in man, alloimmune responses seemed to have a definite influence on the reactivation of latent RCMV after lung transplantation.
The early diagnosis and effective treatment of cytomegalovirus (CMV) pneumonia remains a keystone for patient survival after lung transplantation. At present, the use of DHPG (ganciclovir sodium) opens the possibility of a potent antiviral therapy. The use of monoclonal antibodies directed to immediate early CMV antigens offers a fast method to detect the early phase of systemic or local viral replication. Five single lung and heart-lung transplant patients at high risk for CMV infection (donor, CMV-positive; recipient, CMV-negative) were monitored by cellular immunohistology for immediate early antigens. Specimens from bronchoalveolar lavage (n = 39) and bronchial biopsies (n = 17), and peripheral blood leukocytes (n = 57) were examined. In peripheral blood leukocytes and bronchial biopsy specimens no CMV-positive cells were detected. The bronchoalveolar lavage analysis of two patients showed immediate early antigen-positive cells after 1 to 3 months. At the same time the patients had clinical symptoms that could also be related to lung rejection. Serologic conversion (CMV-IgM) occurred only 6 days later in one patient with informative follow-up analysis; CMV culture (available 4 to 6 weeks later) confirmed the diagnosis retrospectively. DHPG treatment was started immediately and resulted in CMV antigen negativity in bronchoalveolar lavage fluid after one or two courses (10 mg/kg/day; 14 days). Direct antigen detection offers a fast and specific monitoring of early CMV infection. The implications to the clinical management of lung transplant patients are discussed.
Acute lung rejection after orthotopic left lung transplantation and Mycoplasma pulmonis infection were studied immunohistologically by bronchoalveolar lavage (BAL) in inbred rats using monoclonal antibodies differentiating lymphocyte and macrophage subpopulations. Twenty transplants in a major histocompatibility complex (MHC)-different strain combination (Brown-Norway/Lewis) were examined 2, 4, and 6 days after transplantation. Thirty isotransplants (Lewis/Lewis) and normal Lewis rats were used as controls. Eight Lewis rats with acute Mycoplasma pulmonis infection and six Lewis rats with chronic Mycoplasma infection also underwent BAL. Mononuclear cell subpopulations were analyzed using a panel of monoclonal antibodies to MHC and macrophage differentiation antigens: ED1 monocyte/macrophages, ED2 inflammatory tissue macrophages, OX19 T lymphocytes, and OX12 B lymphocytes. The following results were obtained: (1) All allotransplants developed acute rejection on day 2, and it advanced until day 6, demonstrating severe perivascular and peribronchiolar infiltration of inflammatory tissue macrophages (ED1+/ED2+): (2) the proportion and number of inflammatory macrophages (ED2+) in BAL fluid increased on day 6; (3) in BAL the proportion and number of T lymphocytes (OX19+) increased more prominently than B lymphocytes (OX12+) on day 6 of acute rejection; (4) in infection with Mycoplasma pulmonis the increase of T lymphocytes (OX19+) in BAL was more prominent than that of B lymphocytes (OX12+). In conclusion, serial analysis of macrophage, T- and B-lymphocyte antigens was performed. The increase of the proportion of inflammatory macrophages (ED2+) and lymphocytes (OX19+, OX12+) in BAL fluid occurred rather late in the rejection response. This limits the use of BAL as an early diagnostic method of allografted lung rejection.(ABSTRACT TRUNCATED AT 250 WORDS)
Changes in major histocompatibility complex (MHC) antigen expression after heart transplantation were investigated in 233 cardiac allograft biopsy specimens of 33 patients by means of immunohistologic examination. The altered tissue expression was related to histopathologic and clinical diagnoses. A panel of monoclonal antibodies directed to monomorphic determinants was used for the analysis of MHC antigens, class I (human leukocyte antigens [HLA]-A, B, C, and beta 2 microglobulin) and class II (HLA-DR, HLA-DP, HLA-DQ). Donor and recipient MHC antigen expression (HLA-A and HLA-B) was studied by use of monoclonal antibodies directed to polymorphic epitopes. It was found in 57 of 78 rejection episodes that the induction of class I MHC antigens on the normally negative myocyte membranes was related to the rejection process. Usually the induction was focally associated with lymphocytic infiltrates but in severe rejection was generalized on all myocyte membranes. After effective rejection treatment the class I induction was reversed. Class II (HLA-DR) MHC antigens were induced on most vessel endothelia. During rejection MHC antigens HLA-DP and HLA-DQ also were coexpressed on the endothelia of a few vessels. Donor HLA-A and HLA-B antigens were expressed by endothelial and interstitial cells in comparable density but only in low amounts on myocyte membranes. Recipient interstitial cells infiltrated around vessels with time after transplantation. Most interstitial cells between myofibrils, however, remained those of the donor type until 1 year after transplantation. These results show that cardiac allografts undergo remarkable changes in the expression of MHC antigens during clinical complications after transplantation. Furthermore, the changes in alloantigen composition may influence the clinical course.
In parallel with an ongoing clinical trial in patients with metastatic mammary carcinoma, we compared the three-drug combination of cyclophosphamide, tegafur, and methotrexate with the two-drug combination of cyclophosphamide and tegafur in the murine L1210 leukemia and B16 melanoma models. The obtained data based on a central composite design were calculated by mathematical models, which estimate optimum dose combinations for survival by restricting side effect constraints (loss of weight, leukopenia). The main results were as follows: (a) long-term survival can be reached only by accepting a relatively high toxicity in each case, and (b) in the L1210 model the three-drug combination was superior to the two-drug combination, while in the B16 melanoma cyclophosphamide as a single agent offered the best results. The experimental yields are in accordance with preliminary results of the clinical trial. The mathematical model used offers the possibility of comparing drug combinations in a relatively economic way.
BACKGROUND AND METHODS: Intercellular reactions and cell-matrix interactions are mediated by a number of specific adhesion molecules. For the intravascular reactivity of leukocytes and thrombocytes the endothelial expression of adhesion ligand molecules is of main importance. This condition may be of special relevance for the organ-specific manifestation of immune reactions in heart and lung transplants. The question was investigated as to whether organ-specific differences exist on arterial, venous, and capillary endothelial lining cells in heart and lung transplants and whether this condition is modified during transplant rejection. Transplant biopsy specimens of 24 heart transplant recipients (n = 303) and lung transplant recipients who underwent retransplantation for rejection (n = 4), as well as normal heart (n = 7) and lung tissue (n = 4), were studied. Cell-cell adhesion molecules (intercellular adhesion molecule-1 (CD54) and -2; LFA-3; CD31; vascular cellular adhesion molecule-1; neural cellular adhesion molecule; E-/P-selectin; CD44) and cell-matrix adhesion molecules (very late antigen-1 through -6; CD51) were studied on cryostat sections by means of standard immunohistology. RESULTS: (1) Arterial, venous, and capilary endothelia in lung and heart tissue show a distinct pattern of cell-cell and cell-matrix adhesion molecules: capillary and venous endothelia are in contrast to arterioles negative for vascular cellular adhesion molecule-1 and P-selectin. Arterial endothelia of the lung, in contrast to veins and capillaries, express no receptors for laminin (very late antigen-2 and very late antigen-6). (2) With transplant rejection, an induction of a number of adhesion molecules was noted on all endothelial lining cells in heart and lung transplants (intercellular adhesion molecule-1[CD54], intercellular adhesion molecule-2, lymphocyte function antigen-3, very late antigen-2, and very late antigen-6). Capillaries of the lung, in contrast to heart capillaries, displayed no inducibility of vascular cellular adhesion molecule-1 and E-selectin. In heart transplants, differences between capillaries and arteriovenous endothelia were found for virus-like agent-2 and -3. CONCLUSIONS: These results show a distinct expression of a both cell-cell and cell-matrix adhesion molecules on arterial, venous, and capillary endothelia of heart and lung transplants. This expression may influence the local regulation of leukocyte and thrombocyte adhesion during transplant rejection. Especially lung capillaries show a lack of inducibility for vascular cellular adhesion molecule-1 and E- and P-selectin required for the induction phase of leukocyte adhesion. This lack was not found in heart transplants. This observation may explain differences in intravascular adhesion and infiltration between vessel compartments in hearts and lungs and could be of relevance for therapeutic interventions to modify leukocyte and thrombocyte adhesion, as during transplant rejection and reperfusion damage.
Adhesion molecules play a central role in regulation of the immune response after liver allografting. This review gives an overview of the current knowledge of expression and induction of cell-cell, and cell-matrix adhesion molecules after liver transplantation. The current knowledge on the stepwise generation of tissue inflammation, the differential expression of adhesion molecules on liver endothelia, infiltrating leukocytes, and their induction by cytokines is summarized. New diagnostic options and possible therapeutic strategies by using monoclonal antibodies to adhesion molecules are described.