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N L Tilney

Publications and source records attributed to N L Tilney.

At least 19 recordsLinked to original sources
PubMed1992

Evidence that therapeutic strategies targeted at CD4+ cells modulate accelerated rejection of cardiac allografts in sensitized rats by different mechanisms.

(LEW x BN)F1 cardiac allografts are rejected within 36 hr in LEW rats presensitized with BN skin grafts 7 days earlier (acute rejection occurs within 8 days). We have previously described the effects of individual CD4 (BWH-4), CD25 (IL-2R, ART-18) mAbs, and CsA therapeutic regimens upon cardiac allograft survival in sensitized hosts. The present studies were designed to probe an adjunctive use of ART-18 or CsA upon BWH-4-mediated suppression of accelerated graft injury. Sequential therapy with BWH-4 and ART-18 in the sensitization phase (days -7 to -1) and effector phase (from day 0, the day of cardiac transplant), respectively, prolonged graft survival additively to c. 22 days. Treatment with BWH-4 markedly diminished host humoral response against ART-18 preparation. BWH-4 given in concert with subtherapeutic dose of CsA produced graft survival comparable to that induced by mAb alone (c. 13 days) with concomitant decreased host anti-BWH-4 response. None of the combined regimens affected the frequency of circulating CD4+ cells, as compared with that exerted by BWH-4 monotherapy. Thus this study defines principles and some mechanistic aspects of optimal immunosuppressive strategies potentiating the effects of CD4-targeted therapy.

Animals↗
PubMed1992

Maturing thymocytes in accelerated rejection of cardiac allografts in presensitized rats.

LBNF1 cardiac allografts are rejected within 36 hr in LEW rats sensitized with BN skin grafts 7 days earlier (acute rejection in unmodified hosts = 8 days). We have studied and compared the function and migration patterns of thymocytes one day after engraftment in sensitized recipients, unmodified hosts, and normal naive rats. Thymocytes from animals experiencing accelerated rejection were more mature and functionally active, as shown by a significant elevation in percentage of OX-44+ (CD37+) cells, increased alloreactivity to BN and WF antigens, and proliferative responses to Con A and exogenous IL-2. However, the cells could neither lyse BN targets in vitro nor trigger rejection of otherwise indefinitely functioning test cardiac allografts in immunologically unresponsive T cell-deficient (B) rats after adoptive transfer. The traffic of 111In-labeled thymocytes was then evaluated. The migration index increased significantly during accelerated graft rejection, with thymocytes preferentially circulating in the blood, penetrating peripheral lymph nodes--and, interestingly, migrating back to the thymus. Thus, immunoresponsive and functionally active thymocytes, which lack the ability to recognize primed specific antigen, appear during accelerated rejection of cardiac allografts in sensitized rats. These cells migrate to the periphery, and then return in large numbers to their site of origin, the thymus. Hence, this study describes a novel behavior of thymocytes in the state of host alloreactivity that is distinct from the physiological one in otherwise normal thymus.

Animals↗
PubMed1992

Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection.

A significant proportion of renal allografts fail within several months or years after transplantation, primarily because of chronic rejection. The etiology and pathophysiology of this condition remain unclear. We studied the renal function, morphology, and immunohistology, in parallel, among F344-to-Lewis allografts (n = 23) and isografts (n = 13) over the course of 24 weeks. Only an initial 10-day course of CsA (5 mg/kg/day) was given to both groups to prevent acute rejection. Hypertension did not develop, although awake systolic blood pressure was significantly higher in allografts at the end of the study. Significant differences in urine albumin excretion (UalbV) between isografts and allografts were evident as early as 4 weeks after engraftment but rose dramatically by 20 weeks (3.3 +/- 0.7 vs. 21.2 +/- 3.7 mg/day, respectively, P < .001). This pattern continued until the conclusion of the study (5.0 +/- 1.1 vs. 53.5 +/- 7.6 mg/day, P < .001). Serum creatinine values were only significantly elevated in allografts at 16 weeks, which temporally corresponded to the dramatic increase in UalbV. However, renal blood flow and glomerular filtration rate, measured by paraaminohippurate and inulin clearances, respectively, were significantly lower in allografted organs, at 24 weeks. The frequency of glomerulosclerosis lesions was significantly increased in allografted kidneys at 24 weeks and correlated with UalbV values. Glomerular localization of mononuclear leukocyte subsets were equivalent between allografts and isografts; however, the numbers of interstitial macrophages, CD8+, and pan-T-cells were all significantly greater in allografts at 24 weeks. The infiltration of significantly greater numbers of macrophages and lymphocytes into the tubulointerstitium of the allograft group suggests a mononuclear leukocyte effector cell mediation of the progressive glomerular abnormalities in this model of chronic renal allograft rejection in the rat.

Albuminuria↗
PubMed1992

Experimental graft arteriosclerosis. I. The Lewis-to-F-344 allograft model.

Progressive graft arteriosclerosis is responsible for the majority of late deaths occurring in cardiac transplant recipients. In order to define a model of this disease in the rat, we exchanged heterotopic cardiac allografts between MHC-compatible inbred strains. Lewis rats served as donors and F-344 rats as recipients. Twenty allografts were followed by daily palpation and removed at the time of terminal rejection or on the 120th postoperative day for pathologic study. Sixteen allografts (80%) survived at least three weeks, and five allografts (25%) survived indefinitely. The majority of arteries (greater than 90%) examined demonstrated significant intimal disease; histologic findings in lesions in allografts rejecting at early time points included intense mononuclear cell infiltration of the intima, while lesions in long-term-surviving allografts demonstrated fibrous intimal thickening, which is characteristic of graft arteriosclerosis seen clinically. A limited course of cyclosporine therapy in F-344 recipients increased the incidence of indefinite allograft survival from 25% to 86%, and was associated with a modest reduction in the amount of intimal disease observed. These results suggest that this model should be useful in future studies regarding the pathogenesis and therapy of cardiac graft arteriosclerosis.

Animals↗
PubMed1991

Effects of BWH-4 anti-CD4 monoclonal antibody on rat vascularized cardiac allografts before and after engraftment.

We studied the effects and mechanism of action of BWH-4, an IgG2a mouse antirat CD4 monoclonal antibody that recognizes a distinct epitope on the CD4 molecule, in LEW recipients of (LEW x BN)F1 vascularized heterotopic cardiac allografts. Ten animals received daily injections of 700 micrograms BWH-4 for ten days after engraftment. Median actuarial allograft survival was 37 days for the treated animals compared with 7.5 days for controls (n = 6). There was depletion of peripheral blood CD4+ lymphocytes to 4 +/- 1% one week posttransplant (normal = 48 +/- 4%, n = 6). Six additional animals were treated with a lower dose (100 micrograms) of BWH-4 daily for ten days. Median actuarial allograft survival was 10 days and the circulating CD4+ cells decreased to 30 +/- 6% at one week posttransplant. All six low-dose-treated animals mounted an anti-BN alloantibody response by 3 weeks, while only one of the ten high-dose-treated animals had positive alloantibodies two weeks posttransplant. Lymphocyte-mediated cytotoxicity against donor lymphoblasts was completely abolished in the high-dose-treated animals when compared with acutely rejecting controls. We also used low-dose (100 micrograms) BWH-4 to pretreat eleven experimental animals for 7 days prior to engraftment. The circulating CD4+ cells decreased to only 12 +/- 2% on the day of transplantation and 26 +/- 9% one week posttransplant. However, six (55%) pretreated animals survived more than 55 days. There was a 66% decrease in lymphocyte-mediated cytotoxicity against donor lymphoblasts when compared with acutely rejecting controls. We conclude that the anti-CD4 mAb, BWH-4, prevents acute rejection of vascularized heterotopic rat cardiac allografts; this effect is mediated by depletion of the CD4+ T cell subset, suppression of alloantibody production, and inhibition of lymphocyte-mediated cytotoxicity.

Animals↗
PubMed1979

Transfer of specific unresponsiveness to organ allografts by thymocytes. Specific unresponsiveness by thymocyte transfer.

Prolonged survival of vascularized organ allografts has been produced in unmodified inbred rats by transfer of thymocytes from enhanced, engrafted, syngeneic animals. For these thymocytes to increase significantly the survival of test allografts they must be harvested 6-9 d after transplantation. Thymectomy of the enhanced, engrafted animals during the same critical period causes acute rejection of othewise long surviving grafts. For optimal effect, the enhanced thymocyte donor must be actively and passively immunized and receive a cardiac allograft. The necessity for erythrocytes in the initial active immunization regimen is noted. Additionally, the antigenic specificity of the suppressor effect has been established with two histoincompatible donor rat strains. Cellular and humoral host responses mounted by test graft recipients after thymocyte transfer from enhanced, engrafted donors are different from those mounted either by unmodifed animals acutely rejecting their grafts or by enhanced rats bearing well-functioning grafts. Numbers of T lymphocytes are reduced in the grafted hearts and in the spleens of test graft recipients, a finding paralleled by the complete absence of specific direct lymphocyte-mediated cytotoxicity. In contrast, cytotoxic antibody production, although delayed, is increased in magnitude, peaking around the time of graft rejection. These studies provide evidence that different biological manipulations can modify separate pathways in the complex cellular and humoral responses towards organ allografts. They demonstrate that cellular immunity is critically involved in immunological enhancement of vascularized organ allografts, a phenomenon hitherto considered primarily humoral. It seems clear that cells with suppressor activity are present within the thymus during the early phases of immunological enhancement.

Animals↗
PubMed1979

Immune responses to organ allografts. II. Decreased B cell responses to cardiac allografts in rats pretreated with enhancing, suppressor cell, or T lymphocyte depletion protocols.

Primarily vascularized LBN cardiac allografts transplanted to LEW rats are rejected 6 to 8 days after transplantation. Immunoperoxidase stains for cells producing immunoglobulin (Ig) demonstrate a proliferation of Ig-containing immunoblasts in the splenic red pulp (RP) and peripheral periarterial sheath (PAS) within 2 days after transplantation. These immunoblasts differentiate into plasma cells that triple the RP volume by the time of rejection. By 14 days, the plasma cells are replaced by mitotically active large and small lymphocytes with no demonstrable cytoplasmic Ig. Splenic Ig production is followed by a venous vasculitis in the graft and by the appearance of circulating cytotoxic antibodies 5 days after grafting. Three biological methods of prolonging cardiac graft survival were found to derange this sequence of immunological reactions at different stages. Enhancement by antigen and antibody pretreatment of the recipient elicited a premature production of Ig that subsided and was not reinitiated by cardiac transplantation. Transfer of suppression with thymocytes from enhanced cardiac recipients temporarily inhibited differentiation of splenic B cells into immunoblasts and plasma cells. T cell depletion by thymectomy, irradiation, and bone marrow reconstitution also decreased the plasma cell response, possibly by removing helper cells required to switch IgM production to IgG. These studies reemphasize the importance of Ig production in the complex interaction of immune reactions leading to acute rejection of organ transplants.

Animals↗
PubMed1979

Rejected human renal allografts: recovery and characteristics of infiltrating cells and antibody.

Viable infiltrating host leukocytes have been isolated from 10 rejected human renal allografts, removed 1 to 67 months after transplantation. The cell populations have been identified by surface characteristics and their cytotoxic capacities were assessed. A heterogenous population of cells of host origin accumulated in the grafts, including T and B lymphocytes, Fc+ cells, and macrophages. Using a 51Cr release assay, specific cytotoxicity against donor alloantigens was determined. Cytotoxicity of the infiltrating cells was almost invariably greater than cytotoxicity mounted by recipient peripheral blood lymphocytes. Deletion studies confirmed previous work and suggested that T cells were primarily responsible for cytolysis in early acute rejection; non-T cells more often in late chronic rejection. Antibodies eluted from the grafts demonstrated both specific antidonor and nonspecific activity as well as cross-reacting anti-HLA activity. Allograft morphology was examined and cellular and humoral host responses were assessed. These studies emphasize the complexities of immune responses produced by the host against transplanted tissues.

Antibody Specificity↗