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H Azuma

Publications and source records attributed to H Azuma.

At least 163 records · Page 9Linked to original sources
PubMed1995

Renal mass as a determinant of late allograft outcome: insights from experimental studies in rats.

Experimental studies of renal mass augmentation were conducted in the Fisher-->Lewis rat model of late renal allograft failure to assess the injury attributable to inadequate nephron supply in single allografts. Marked proteinuria, glomerulosclerosis and cellular infiltration developed in bilaterally nephrectomized recipients of single allografts at 16 to 20 weeks. By contrast, recipients with two kidney showed markedly reduced indices of allograft injury, irrespective of whether the second kidney was native or transplanted. Micropuncture whether the second kidney was native or transplanted. Micropuncture study of solitary allografts revealed glomerular hyperfiltration and elevated glomerular capillary pressure with marked inter-nephron variation despite normal systemic arterial pressure. In the two-kidney groups, single-nephron GFR and glomerular capillary pressures were essentially normal. These findings provide unambiguous evidence that the cycle of progressive nephron loss characteristic of extensive renal mass ablation operates in single allografts and contributes significantly to injury. The magnitude of allograft protection obtained by augmenting renal mass attests to the importance of nephron supply as a determinant of injury in this model. We conclude that mass-related injury processes may play a potentially major and underappreciated role in the pathogenesis of late renal allograft failure.

Analysis of Variance↗
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

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

Repeated endothelial removal augments intimal thickening and attenuates EDRF release.

To evaluate the significance of repeated denudation injury in progression of atherosclerosis, we performed a single and then a second balloon denudation on the rabbit carotid arteries. Morphological examinations and organ chamber experiments were performed, and the results were compared. On morphological examinations, reendothelialization was almost completed in 2 wk after redenudation, whereas it required 6 wk after a single denudation. Intimal thickening progressed after redenudation. Organ chamber experiments showed that contractile responses and endothelium-independent relaxation remained unchanged after redenudation. Endothelium-dependent relaxations to acetylcholine, ADP, and substance P decreased progressively by repeating denudation. These relaxation responses were inhibited by NG-nitro-L-arginine, hemoglobin, and methylene blue and were considered to be associated with the production and/or release of endothelium-derived relaxing factor-nitric oxide (EDRF-NO). The diffusion barrier mechanism for the decreased endothelium-dependent relaxations was ruled out using sandwich experiments. In conclusion, repeated endothelial denudation caused progression of intimal thickening and acceleration of endothelial regeneration, and repeated endothelial regeneration resulted in progressively less production and/or release of EDRF-NO.

Acetylcholine↗
PubMed1994

Role of endothelin-1 in neointima formation after endothelial removal in rabbit carotid arteries.

To investigate the role of local endothelin (ET)-1 in neointima formation, we performed a balloon denudation in the rabbit carotid artery. Four weeks after denudation, regeneration of endothelial cells was almost complete, and a marked intimal hyperplasia was observed. The tissue level of ET-1-like immunoreactivity was significantly increased even at 24 and 72 h after denudation and was 9.3 times higher than the control group in 4 wk. On the same time course, the proliferating cell nuclear antigen (PCNA)-positive cells clearly appeared. Receptor density values for 125I-ET-1 and 125I-IRL-1620 [ET-receptor subtype B (ETB)-selective ligand] bindings were significantly greater in the hyperplastic artery without changes in dissociation equilibrium constant values. The 125I-ET-1 binding sites not inhibited with BQ-123 [ET-receptor subtype A (ETA)-selective antagonist] were significantly increased in hyperplastic arteries. ETB receptors were more densely localized in the neointima. The chronic intravenous administration of BQ-123 at plasma concentrations sufficient to antagonize the ETA receptors had no effect on neointima formation and the appearance of PCNA-positive cells. We concluded from all results that ET-1 would be involved in neointima formation after endothelial removal and that the ETA receptors would not play a role in this process.

Animals↗