Search PubMed⌕ Search

Biomedical subjects

S G Tullius

Publications and source records attributed to S G Tullius.

At least 73 records · Page 4Linked to original sources
PubMed1995

Binding of lymphocytes to acutely rejecting rat kidney allografts in vitro is guided by events in the graft itself rather than by sensitization of host lymphocytes.

Circulating host lymphocytes recognize, bind to, become activated by, and infiltrate engrafted allogeneic tissues. The mechanisms responsible for these early events which lead to acute immunological rejection have not been precisely defined. We have examined sequentially in vitro lymphocyte binding patterns in a kidney transplant model of acute rejection in rats and their relationship to the expression of two representative adhesion molecules, ICAM-1 and LFA-1. The extent of binding of naive, or allosensitized recipient strain LNL or PBL, or donor strain or third party cells to frozen sections of kidney allografts was not significantly different; adherence was dependent upon whether the graft was an allograft or an isograft. The pattern of lymphocyte adherence to various allograft compartments was distinct and varied with time. Within 3 days after transplantation only a few cells had bound to the frozen tissues, preferentially to vascular endothelium. By days 5 and 7, increasing numbers of cells bound primarily to tubules, as did the few cells adhering to isografts. Immunohistologically, ICAM-1 expression increased progressively during acute rejection, first on vascular endothelium, later on tubules. LFA-1+ infiltrating cells peaked more quickly. Lymphocyte binding could be inhibited (approx. 40%) by monoclonal antibodies directed against LFA-1 and ICAM-1. The results indicate that in vitro lymphocyte binding to acutely rejecting kidney transplants is directed by the allogenicity of the graft itself via upregulation of adhesion molecules rather than sensitization of the host cells.

Acute Disease↗
PubMed1994

The contribution of reduced functioning mass to chronic kidney allograft dysfunction in rats.

Chronic renal allograft dysfunction may become manifest months or years after transplantation by progressive functional deterioration associated with morphological changes that include vascular obliteration, glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Two hypotheses have evolved to explain the etiology of this process, usually described as "chronic rejection:" first, that it is primarily an antigen-dependent phenomenon influenced by continuing host alloresponsiveness; second, that nonimmunological, alloantigen-independent factors contribute to the progressive changes. Using an established model of chronic rejection of kidney transplants in rats in which the lesions progress relentlessly over time, we have determined the long-term effects of superimposing renal mass reduction on the indices of progressive allograft injury. Increasing proteinuria, a reproducible index of kidney graft dysfunction, developed after 12 weeks in all recipients of intact allografts, but was accelerated in kidneys with reduced mass, regardless of whether the organ was allogeneic or isogeneic. The coincident infiltration of macrophages and expression of cytokines and growth factors were associated with the development of glomerular sclerosis and interstitial fibrosis; such functional and morphological alterations occurred in an accelerated manner in all reduced-mass kidney allografts and isografts. Conversely, intact allografts in recipients also bearing a retained native kidney never manifested any chronic changes throughout the entire follow-up period. These findings emphasize the role of alloantigen-independent factors, particularly reduced renal mass, in the multi-factorial etiology of "chronic rejection" of kidney transplants.

Animals↗
PubMed1994

Reversibility of chronic renal allograft rejection. Critical effect of time after transplantation suggests both host immune dependent and independent phases of progressive injury.

The characteristic and progressive morphological changes of glomerulosclerosis, interstitial fibrosis, and vascular obliteration that occur in renal allografts experiencing chronic rejection correlate directly with declining function and eventual graft loss. Using an established rat transplant model of chronic rejection where such changes occur in predictable sequence, allografts were retransplanted back into the donor strain at serial intervals after the initial engraftment to determine at what stage of development the lesions could still be reversed by removing the continuing immunological drive of the host. Morphological changes were compared with those in retransplanted isografts and nonretransplanted allografts at comparable time intervals. Histological and immunohistological characteristics of chronic rejection were reversible by retransplantation at or later than week 12 could not reverse the intense humoral and cellular immune responses, or the structural changes (particularly fibrosis) that developed after that period. However, the sparse but inevitably progressing cellular infiltration and cytokine expression in retransplanted and nonretransplanted isograft controls suggest the persistent influence of alloantigen-independent factors in addition to those of host immunity. Thus, the early stages of chronic rejection are alloantigen dependent and reversible, whereas the later changes were irreversible and alloantigen-independent factors appeared increasingly important.

Animals↗
PubMed1994

Infiltration patterns of macrophages and lymphocytes in chronically rejecting rat kidney allografts.

The migration of circulating leukocytes to sites of inflammation or antigen is based, at least in part, on the activities of adhesion molecules. In the context of organ transplantation, some of these have been shown to be upregulated during acute allograft rejection. As their role during chronic rejection has not been examined, we have used an established rat model to compare sequentially the presence of host cells within the grafts, as defined immunohistologically, with patterns of in vitro leukocyte binding and their dependence upon particular adhesion molecules. Various donor populations of peripheral blood lymphocytes (PBL), lymph node lymphocytes (LNL), and splenic monocytes were interacted with snap-frozen sections of allografted, isografted, and native kidneys at serial intervals up to 24 weeks after transplantation. Monocyte binding in the allografts rose at 8 weeks and peaked at 12 weeks, a period preceding the maximum numbers of macrophages noted immunohistologically in the chronically rejecting grafts at 16 weeks. Lymphocyte binding and infiltration patterns were similar, remaining stable throughout the follow-up period and consistently greater than those noted in isografts. In vitro binding of the monocytes was inhibited by mAbs against ICAM-1, LFA-1, CD18, and MAC-1; MAC-1 did not influence lymphocyte binding, although the other mAbs were effective. We conclude that adhesion molecules are responsible, at least in part, for patterns of cell populations infiltrating chronically rejecting renal allografts.

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

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↗