Biomedical subjects
N L Tilney
Publications and source records attributed to N L Tilney.
Anti-interleukin 2 receptor monoclonal antibodies spare phenotypically distinct T suppressor cells in vivo and exert synergistic biological effects.
The therapeutic efficacies of ART-18, ART-65, and OX-39, mouse antibodies of IgG1 isotype recognizing distinct epitopes of the p55 beta chain of the rat IL-2-R molecule, were probed in LEW rat recipients of (LEW X BN)F1 heterotopic cardiac allografts (acute rejection in untreated hosts occurs within 8 d). A 10-d course with ART-18 prolongs graft survival to approximately 21 d (p less than 0.001). Therapy with ART-65, but not with OX-39, was effective (graft survival approximately 16 and 8 d, respectively). Anti-IL-2-R mAb treatment selectively spared T cells with donor-specific suppressor functions; the CD8+ (OX8+ W3/25-) fraction from ART-18-modified recipients, and primarily the CD4+ (W3/25+ OX8-) subset from ART-65-treated hosts conferred unresponsiveness to naive syngeneic rats after adoptive transfer, increasing test graft survival to approximately 16 and 45 d, respectively. Concomitant administration of ART-18 and ART-65 to recipient animals in relatively low doses exerted a strikingly synergistic effect, with 30% of the transplants surviving indefinitely and 50% undergoing late rejection over 50 d. These studies provide evidence that anti-IL-2-R mAbs selectively spare phenotypically distinct T cells with suppressor functions. The data also suggest that in vivo targeting of functionally different IL-2-R epitopes may produce synergistic biological effects.
Synergy between subtherapeutic doses of cyclosporine and immunologic enhancement in rat recipients of cardiac allografts.
We have analyzed the adjunctive effect of subtherapeutic doses of cyclosporine (CsA, 1.5 mg/kg/day x 7 or 14 days) on cardiac allograft survival in actively and passively enhanced rats. This CsA dose, one tenth of the effective dose, when administered after, but not before, transplantation into enhanced hosts produced permanent graft acceptance; cardiac allografts survive c. 25 days in recipients enhanced only and 1 week in untreated animals. Adoptive transfer of spleen T cells of OX8+ or W3/25+ phenotype from long-term (greater than 200 days) graft recipients prolonged donor-specific test graft survival in naive rats (c. 16 days and c. 14 days, respectively, P less than 0.001) and delayed rejection in reconstituted B rats from 7 days to 21-23 days (P less than 0.001). Indeed, both T subsets were separately equally potent and with no overlap responsible for the suppressor activity. The phenotypic profile of the immune cells in the maintenance phase of enhanced or enhanced + CsA-treated recipients was comparable to naive or isografted controls as demonstrated by flow cytometry and immunohistologic studies. Furthermore, the activation status of the graft infiltrate in long-term survivors was similar regardless of the initial immunosuppressive protocol. CsA contributed selectively to the enhancing regimen in the induction phase of unresponsiveness, diminishing the cellularity of graft infiltrate and preventing intragraft T cell activation. These studies stress synergy between subtherapeutic doses of CsA and immunologic active/passive enhancement, 2 immunosuppressive modalities that spare T cells with suppressor capabilities but differ in the inhibition of T helper cell activation.
Synergy between subtherapeutic doses of cyclosporine and immunobiological manipulations in rat heart graft recipients.
Cyclosporine in combination with other chemical or biological immunosuppressive modalities has been useful in clinical and experimental organ transplantation. In these studies, the efficacy of adjunctive subtherapeutic doses of CsA given to immunologically enhanced heart graft recipients or to animals treated with an anti-IL-2 receptor monoclonal antibody (ART18) are described. Individually, the treatment entities are only partially effective. In rats undergoing active and passive enhancement alone, heart allograft survival was increased to 25 +/- 12 days in two-thirds, indefinitely in one-third. After ART18 treatment, grafts survive 21 +/- 1 days. Grafts are accepted permanently in animals receiving full-dose CsA (15 mg/kg X 7), but are rejected acutely (c. 7 days) when subtherapeutic doses (1.5 mg/kg X 7) are used. However, when subtherapeutic doses of CsA are given in combination with immunological enhancement or with interleukin-2-receptor-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy spare selectively T cells with suppressor activity in vivo; in enhanced animals, the W3/25+ subset is responsible for prolonged graft survival, the OX8+ fraction is responsible in ART18-treated animals and in CsA-treated animals. Both subpopulations show suppressor activity in the later stages of combination treatment. IL-3 production is increased significantly in these states of unresponsiveness, an observation also noted during maintenance CsA treatment; this seems to correlate with suppressor activity. Immunoperoxidase studies of the graft infiltrates emphasize the synergistic effects of combination treatments. Thus, subtherapeutic doses of CsA plus biologic host manipulations produce greatly increased graft survival by affecting selectively different host immune mechanisms.
Interleukin 2 receptor-targeted therapy--rationale and applications in organ transplantation.
Despite major advances in immunopharmacology for use in clinical organ transplantation, graft rejection and drug-induced side effects remain the major problems with currently available immunosuppressive modalities. Recent advances in hybridoma technology have produced relatively effective and reproducible biological immunosuppression with monoclonal antibodies; indeed, OKT3 and anti-T12 mAbs have been employed with considerable success as adjuncts to chemical suppression in treating rejection. Nonetheless, the use of such antibodies broadly reactive to differentiation antigens on T lymphocytes does not solve the problems of side effects caused by general immunosuppression. An ideal therapeutic agent should target only lymphocytes that participate in rejection of foreign tissue without affecting physiological host immune surveillance and normal defense mechanisms. Theoretically, this goal could be achieved by "antigenic suicide," or by using the appropriate antiidiotypic antibodies or mAbs against the antigen combining site of T cell receptors. However, because of the intense polymorphism of transplantation antigens and the vast genetic repertoire encoding for the T cell antigen receptor, success of such forms of specific immunosuppression, at least at this time, is highly improbable.
A further analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus immune globulin: interim comparison of a randomized and an open-label trial.
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Suppressor cells influence maintenance and reversal of late rejection in indefinitely surviving skin allografts in cyclosporine-treated rats.
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Synergistic immunosuppressive effect of subtherapeutic doses of cyclosporine A on immunologic enhancement in rat recipients of cardiac allografts.
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Inhibition of allograft rejection and organ-specific autoimmune disease by anti-interleukin-2 receptor (IL-2R)-targeted immunotherapy. The action of anti-IL-2R monoclonal antibodies and synergistic effect of cyclosporin A.
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Anti-interleukin 2 receptor monoclonal antibody therapy in rat recipients of cardiac allografts: the role of antibody isotype.
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Modulation of accelerated rat cardiac allograft rejection by cyclosporine and ART-18.
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Pharmacologic and immunologic agonists and antagonists of cyclosporine.
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Late development of intractable lymphocele after renal transplantation.
A case of lymphocele occurring 7 years after kidney transplantation and leading to intractable ascites and recurrent pleural effusion is presented. Ultrasound was used extensively for diagnosis, diagnostic sampling, and monitoring of resolution and recurrence. Invasive approaches to definitive therapy, including internal drainage and ligation of lower extremity lymphatics, alleviated the local problem of a lymphocele but led to recurrent ascites and symptomatic pleural effusions. A Denver shunt,reportedly helpful in cirrhotic and oncologic patients, was successfully employed to decompress the ascites and effusion of this patient. The pathophysiology and treatment of lymphoceles and the management of peritoneovenous shunts is discussed.
Immunohistologic profile of cells infiltrating acutely rejecting and long-surviving rat cardiac allografts.
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[Immunosuppressive therapy in transplantation surgery].
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Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients.
We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.
Two phenotypically distinct populations of T cells have suppressor capabilities simultaneously in the maintenance phase of immunologic enhancement.
The events leading to immunologic enhancement in LEW rats immunized actively with Brown Norway (BN) rat spleen cells and passively with LEW anti-BN hyperimmune serum 11 and 10 days before receiving (LEW X BN)F1 cardiac allografts, respectively, have been studied. Cellular suppressor mechanisms developing during the induction phase of this phenomenon have recently been shown to be mediated by W3/25+ T cells in an antigen-specific manner. The present study suggests that the late maintenance phase of immunologic enhancement is mediated in vivo by simultaneously present separate donor-specific T cell subpopulations of W3/25+ and OX8+ phenotypes. Splenocyte subsets from grafted recipients greater than 100 days after transplantation were adoptively transferred into unmodified syngeneic LEW rats that received a specific test allograft 24 hr later, or into B recipients bearing indefinitely surviving heart grafts. Test graft survival was prolonged significantly in the first group and not altered in the second. Indeed, nonoverlapping W3/25+ and OX8+ cell fractions were separately responsible for suppression. However, when suppressor activity was tested in vitro in a three-component coculture mixed lymphocyte reaction, no suppression by T cells was obtained; this lack of correlation between in vivo and in vitro results has also been noted by other investigators in different systems. Thus, in the maintenance phase of actively and passively induced immunologic enhancement, interplay between two phenotypically distinct T cells with suppressor characteristics, but not putative cell-surface blocking factors, seems to prevent development of an alloreactive response and mediate host unresponsiveness.
W3/25+ T cells mediate the induction of immunologic unresponsiveness in enhanced rat recipients of cardiac allografts.
Cellular suppressor mechanisms developing during the induction of immunologic enhancement were studied in LEW rats immunized actively with BN spleen cells and passively with LEW anti-BN hyperimmune serum 11 and 10 days before receiving a (LEW X BN)F1 cardiac allograft, respectively. With this regimen, graft survival is prolonged from 7.4 +/- 0.5 days in unmodified, acutely rejecting hosts to 25 +/- 12 days in enhanced recipients, with one-third of the grafts surviving indefinitely. To test for suppressor capacities, 60 X 10(6) splenic T helper/inducer (W3/25+) and T suppressor/cytotoxic (OX8+) cells were adoptively transferred 7 and 14 days after transplantation either into unmodified syngeneic LEW animals that received (LEW X BN)F1 test grafts 24 hr later or into T cell-deprived B rats with indefinitely functioning heart transplants that were reconstituted with sensitized lymph node cells (100 X 10(6). W3/25+ T cells harvested on days 7 and 14 from enhanced recipients prolonged test graft survival in unmodified hosts (13.1 +/- 2.3 and 13.3 +/- 1.3 days, respectively, p less than 0.001) and delayed rejection in reconstituted B rats from 6.7 +/- 0.5 to 18.2 +/- 6.5 and 23.3 +/- 5.8 days, respectively (p less than 0.001). OX8+ and B lymphocytes had no suppressor activity. However, enzymatic stripping of the surfaces of W3/25+ cells abrogated suppressor function. Similarly, after i.p. treatment with cyclophosphamide, W3/25+ T cells lost their suppressor properties. Lack of donor specific but not third party alloaggressiveness was demonstrated by the profoundly diminished ability of W3/25+ lymphocytes from enhanced hosts to recreate rejection in nonreconstituted B rats, even when exogenous interleukin 2 was administered. After pronase treatment, however, W3/25+ T cells were capable of inducing immunoresponsiveness at a tempo similar to naive T helper cells (31.5 +/- 12.5 vs 32.8 +/- 7.9). Thus, the present studies provide evidence for the development of a specific W3/25+ suppressor cell in the induction of active and passive enhancement. Coincident abrogation of specific T effector alloaggressiveness is apparently mediated by surface-blocking factors.