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N L Tilney

Publications and source records attributed to N L Tilney.

At least 91 records · Page 5Linked to original sources
PubMed1994

Chronic graft rejection.

Although chronic rejection remains the most crucial cause of organ graft loss over the long term, its etiology is not well defined. Early injury to graft endothelial cells caused by alloantigen-independent factors, such as ischemia or reperfusion, as well as alloantigen-dependent events, such as acute rejection, have been implicated. Macrophages and their products, peptide growth factors and adhesion molecules are all thought to play an important role in this process via the cytokine-adhesion molecule cascade. Although new immunosuppressive agents, including RS61443 or rapamycin, may be effective in preventing antigen-driven components of this condition, risk factors for initial non-immune injury must also be considered and, if possible, countered.

Animals↗
PubMed1994

Adhesion molecules and transplantation.

OBJECTIVE: Accessory adhesion molecules are thought to influence the first interaction between host leukocytes and graft vascular endothelial cells. Their role in transplantation is reviewed. SUMMARY: Adhesion molecules have been divided into three major families: the selectins, the integrins, and the immunoglobulin superfamily. Selectins are small proteins that mediate the first contact between stimulated endothelial cells and leukocytes. Integrins interact with cytoskeletal components of cells, presumably coordinating extracellular stimuli with cytoskeleton dependent actions, such as motility, shape change, and phagocytic responses. Members of the immunoglobulin superfamily are structurally homologous, although they do not necessarily share similar functions. They are involved in T-cell proliferation and intracellular events. METHODS: Various groups of investigators have studied the influence and expression of adhesion molecules following transplantation. The authors of this article have reviewed and summarized the available literature. RESULTS: Many different adhesion molecules are up-regulated during the rejection event. Treatment of transplant recipients with monoclonal antibodies against accessory molecules, such as leukocyte function associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), has resulted in either a prolongation of transplant survival or the induction of tolerance in some models. Other interventions are under study. CONCLUSION: By mediating the initial leukocyte/endothelial cell interactions, adhesion molecules may play an important role in graft rejection, mediation of infiltration into the graft, and dissemination of the antigenic message to the lymphoid tissues of the host. Future studies will have to deal not only with conceptualizing their function and mechanisms of action, but also with manipulating their interrelationships to the benefit of the graft recipient.

Animals↗
PubMed1994

Long-term kidney isografts develop functional and morphologic changes that mimic those of chronic allograft rejection.

OBJECTIVE: This study examined antigen-independent factors in the pathogenesis of chronic rejection of organ transplants. SUMMARY BACKGROUND DATA: In addition to alloantigen-dependent events, antigen-independent factors can influence chronic rejection of organ allografts. Initial injury, including early ischemia and acute rejection, may contribute. METHODS: Kidney isografts were transplanted orthotopically into bilaterally nephrectomized rat recipients and studied functionally, morphologically and immunohistologically, at serial intervals up to 72 weeks after transplantation. Controls included chronically rejecting kidney allografts using a well-established model, non-nephrectomized and uninephrectomized animals with a native kidney that had undergone initial ischemia and uninephrectomized rats whose remaining kidney had been manipulated operatively. RESULTS: Allograft recipients developed progressive proteinuria after 12 weeks, with gradual renal failure ultimately leading to death. At the same time, morphologic changes, including progressive arteriosclerosis and glomerulosclerosis, tubular atrophy, and interstitial fibrosis, developed. Immunohistologically, macrophages infiltrated glomeruli during this period and cytokines became upregulated. Comparable changes occurred in isografts, but later, beginning after week 24 and progressing thereafter. The single ischemic kidney in uninephrectomized controls also developed the same lesions; no comparable changes were noted in other control kidneys. CONCLUSIONS: Antigen-independent functional and morphologic changes occur in long-term kidney isografts that resemble those appearing considerably earlier in allografts that reject chronically. Initial injury and extent of functioning renal mass may be important factors for such late changes.

Animals↗
PubMed1994

The role of leukocyte adhesion molecules in acute transplant rejection.

The specific adhesion of cells to other cells or to particular tissues or tissue components is a basic function of cell migration and recognition and underlies many biologic processes including embryogenesis, repair, and immunity. Adhesion molecules are involved in and mediate most cell to cell interactions, implement migration of leukocytes to inflammatory or alloantigenic sites, and costimulate well activation and transformation. Because of these functions, the subject of adhesion molecules is gaining broader interest in the field of transplantation, particularly in the conceptualization and development of future treatment strategies. These molecules influence not only the first interaction between host leukocytes and vascular endothelial cells of the graft but also their migration through the grafted tissues. These contacts seem to be based initially on antigen-independent events of adhesion, which then progress to the antigen-dependent events of antigen recognition and host cell activation. This review evaluates current studies concerning the role of adhesion molecules in the context of the multifaceted processes of allograft rejection.

Acute Disease↗
PubMed1994

Alloantigen-independent factors lead to signs of chronic rejection in long-term kidney isografts.

Chronic rejection is the most important cause of graft failure after the first year of transplantation. In addition to the effects of host immunological injury, antigen-independent factors may gain in importance over the long term. We therefore assessed the influence of such factors on rat kidney isografts functioning for prolonged periods and compared our findings with those observed in naive control rats and in allograft recipients. Functional, morphological, and immunohistological changes in the isografts became obvious 32 weeks after engraftment, and by 52 weeks the findings mimicked those of chronic allograft rejection. As allografted kidneys sustained these changes earlier on and more intensely, both alloantigen-independent and -dependent factors are thought to be implicated in this process.

Animals↗
PubMed1994

Host leukocytes and their products in chronic kidney allograft rejection in rats.

Bilaterally nephrectomized Lewis recipients of Fisher 344 (F344) kidney allografts, treated with CyA (1.5 mg/kg/day x 10), develop progressive changes of chronic rejection. Treated F344-to-F344 acted as isograft controls. Proteinuria was determined sequentially. Grafts were harvested 8, 12 and 16 weeks after transplantation (n = 9/group/time period). Infiltrating host cells and their products were assessed in chronically rejecting grafts by histology and immunostaining using mAbs for monocyte/macrophages, T-cells, ICAM-1, LFA-1 and cytokines. For in vitro binding studies, snap-frozen sections of transplanted kidneys were incubated with monocytes/macrophages and lymphocytes isolated from peripheral blood (PBL) of naive animals. For in vivo migration studies, naive cell populations were labeled with Bis-Benzamide and transferred i.v. to grafted animals at weeks 8, 12 and 16 (n = 3/group); grafts were harvested 24 h later and cell localization assessed under immunofluorescence. Increasing numbers of ED1 + monocytes/macrophages in allografted kidneys peaked at 16 weeks, localizing preferentially in glomeruli, where IL-1, IL-6 and TNF-alpha expression had also become intense and correlated with progressive glomerulosclerosis. Binding studies corroborated these results. In vitro, a few monocytes/macrophages bound to glomeruli and vessels at 8 weeks; by 12 weeks, binding to glomeruli was high (72% of cells). In vivo, large numbers of transferred labelled monocytes/macrophages were found in kidney allografts at 12 weeks (23%, isografts; < 7%, P < 0.01). In contrast T cells (primarily CD4+) were a consistent feature in allografts elevated as compared to isografts and correlating with in vitro and in vivo binding patterns; associated cytokines included IL-2, IFN- and TNF-alpha. Functional data followed these results: urine protein excretion by allograft recipients increased from baseline at 8 weeks (12 mg/day) to > 50 mg/day at 16 weeks at which point animals were beginning to die of renal failure; proteinuria in isografted rats did not increase during this time period. These results suggest that monocyte/macrophage and CD4+ T cells and their products are important in chronic kidney allograft rejection, contributing to the progressive sclerosis and fibrosis.

Animals↗
PubMed1994

The relationship between reduced functioning kidney mass and chronic rejection in rats.

Interest has recently increased in the role of alloantigen-independent factors in chronic rejection. In this context, we examined the long-term effects of reduced functioning kidney mass in a F344-->LEW allograft (A) model. Animals were divided into three groups depending upon the amount of retained kidney. Renal arterial branches in the hilus were ligated so that one-third or two-thirds of the graft remained viable (1/3 and 2/3 groups, respectively); organs were left intact in the third (3/3) group. Urine protein concentrations were determined 4, 6, 8 and 10 weeks after engraftment and organs (five/group/time) were harvested and examined morphologically and immunohistologically. Proteinuria increased progressively in all 1/3, 2/3 and 3/3A animals, but faster in those with reduced kidney mass. This functional decline correlated well with increasing numbers of macrophages followed by interstitial fibrosis and glomerular sclerosis, which had become prominent by week 6 in group 1/3A and by 8 weeks in groups 2/3A and 1/3I (I, isografted), with animals beginning to die. IL-1, IL-6 and TNF production correlated well with the location and number of macrophages in all groups. These results suggest that kidney mass exerts a significant alloantigen-independent influence on chronic rejection. Allogenicity of the graft accelerates and amplifies the process.

Animals↗
PubMed1994

Nephron supply is a major determinant of long-term renal allograft outcome in rats.

The effects of augmenting the nephron supply on indices of allograft injury were assessed in a rat model of "chronic rejection." Orthotopic renal allotransplantation into unine-phrectomized rats was followed by excision (allograft-alone group) or preservation of the remaining native kidney (allograft+native kidney group) such that the total kidney complement was either the allograft alone, or the allograft plus one retained native kidney. After 18 wk, values for GFR (1.85 +/- 0.3 ml/min) and kidney weights (2.3 +/- 0.2 g) in allograft-alone rats were far in excess of corresponding values in the allograft of allograft+native kidney rats (0.88 +/- 0.1 ml/min and 1.1 +/- 0.5 g, respectively). Proteinuria (35 +/- 2 mg/d) and allograft glomerulosclerosis (24 +/- 8%) also characterized allograft-alone but not allograft+native kidney rats, in whom glomerular structure (allograft glomerulosclerosis, 4 +/- 1%; native kidney glomerulosclerosis, 0%) and glomerular functional integrity (proteinuria 7 +/- 0.7 mg/d) were well preserved. Thus, the observed allograft protection derived from the presence of a retained recipient native kidney supports the hypothesis that a single renal allograft contains insufficient nephrons to prevent progressive renal injury, implicating nephron supply as a major determinant of long-term allograft outcome.

Animals↗
PubMed1994

Cytokines and adhesion molecules in chronic rejection.

Despite the increasing short-term success of clinical transplantation during recent years, many allografts, regardless of organ type, continue to be lost over the long term due to chronic rejection, despite improvements in immunosuppression and better patient management. Thus, as a long-term answer to an irreversible disease process, organ transplantation has not lived up to its potential. Although the host mechanisms leading to the process remain obscure, the progressive morphological changes evolving in the afflicted organs are well understood. Chronic rejection has long been thought to be an antibody-mediated event, as immunoglobulins and other circulating proteins are often associated with areas of vascular damage. It is becoming more clear, however, that a whole array of host defense factors, primarily, cytokines, lymphokines and adhesion molecules, are of critical importance in the process. This review summarizes various cytokines and their individual functions as well as adhesion molecules potentially involved in aspects of immune responsiveness, and placed in the context of chronic rejection.

Cell Adhesion Molecules↗
PubMed1993

Cytokines, adhesion molecules, and the pathogenesis of chronic rejection of rat renal allografts.

Little is known of the host immune mechanisms responsible for initiation and progression of chronic rejection. We describe immunopathologic features associated with progressively deteriorating function of kidney allografts in the F344-to-Lewis rat strain combination, which differ at MHC and non-MHC loci. Initial rejection in untreated recipients was controlled by a brief course of CsA (5 mg/kg/day, for 10 days), resulting in > 80% of recipients surviving up to a year despite declining renal function. In contrast to controls (isografts placed in untreated or CsA-treated Lewis rats), allografts from 12-16 weeks post-Tx showed segmental or global glomerulosclerosis, increasing tubular atrophy, interstitial fibrosis, and intimal proliferation leading ultimately to vascular occlusion. By flow cytometry, IgM and IgG alloantibodies peaked at 2-4 weeks, with a gradual decline to baseline thereafter. Immunohistology showed early and progressive deposition of IgM, IgG, C3, and fibrin in vessel walls and glomeruli. In addition, by 12 weeks, extensive infiltration by activated (IL-2R+) macrophages and CD4+ T cells were noted in glomeruli and blood vessels, in conjunction with staining for the cytokines TNF-alpha, IL-1, and IL-6. The persistent and dense intraglomerular expression of IL-6 was of particular interest, given its potent mitogenic effects for mesangial cells in vitro, and suggests a role for this cytokine as a mediator of mesangial expansion, advanced glomerular injury, and glomerulosclerosis in chronic rejection. Parallel timing of IL-6 and TNF-alpha expression was shown in serum samples by ELISA and bioassays. In vitro binding studies showed increased binding of naive host lymphocytes to allograft versus isografts, correlating with upregulation (peaking at week 16) of intercellular adhesion molecule-1 expression by graft endothelium. We conclude that cytokine production and upregulation of adhesion molecules occurring as part of a cellular immune response may be as important to the etiology of chronic rejection as the hitherto widely emphasized antibody-mediated host responses.

Animals↗
PubMed1993

Iron chelation suppresses mononuclear cell activation, modifies lymphocyte migration patterns, and prolongs rat cardiac allograft survival in rats.

Iron influences host immunity, in part by affecting the function and migration patterns of T cell subpopulations. Removal of iron stores from the body by chelation decreases proliferation and differentiation of T cells, as shown in models of autoimmunity and pancreatic islet transplantation. We have examined the influence of iron chelation on rejection of vascularized heart allografts in rats. Two protocols were investigated: "treated" recipients received desferrithiocin (30 mg/kg/day) orally for 10 days beginning the day of transplantation; "pretreated" hosts received a similar dose of the drug for 10 days before engraftment. Graft survival increased from about 7 days in untreated animals to 14-16 days in both treatment groups (P < 0.001). Histological and immunoperoxidase studies of allografts at day 7 showed that iron chelation resulted in only a mild reduction in cell infiltration, but in a marked decrease in graft edema and interstitial hemorrhage and essentially complete suppression of mononuclear cell activation and cytokine production. Chelation therapy was also found to inhibit profoundly cytokine (TNF-alpha) production in rats treated with LPS, consistent with the effects observed in situ in the allografts. In vitro studies showed that pretreatment significantly inhibited the mixed lymphocyte reaction. Chelation also influenced migration of T lymphocyte subsets: treatment stimulated migration of CD4+ lymphocytes to peripheral lymph nodes; pretreatment strikingly and selectively increased CD8+ cell migration into parathymic lymph nodes draining the graft, with the opposite effect on nondraining node groups. We conclude that treatment with iron-chelating agents has several effects on host alloresponsiveness in a rat heart graft model secondary to inhibition of immune activation; these include prolongation of graft survival, inhibition of the mixed lymphocyte reaction (pretreatment), marked depression of cytokine production, and alteration in recirculation patterns of lymphocyte subpopulations.

Animals↗