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N L Tilney

Publications and source records attributed to N L Tilney.

At least 145 records · Page 8Linked to original sources
PubMed1989

Biodistribution of anti-interleukin 2 receptor monoclonal antibodies correlates with their therapeutic efficacy following transplantation.

IL-2R-targeted therapy prevents graft rejection in various experimental models and in man. However, the principles of optimal mAb selection remain elusive, as their efficacy in vivo does not always correlate with their characteristics in vitro. ART-18 and OX-39, mouse IgG1 mAbs, define distinct epitopes on the p55 subunit of the rat IL-2R. Treatment of LEW hosts with ART-18 prolongs survival of LBN cardiac allografts up to a month; in contrast, OX-39 never affects acute (8-day) rejection. In this study, we evaluated the biodistribution of 125I-labeled ART-18 and OX-39 administered iv to untreated and heart-grafted rats. ART-18 was cleared from the circulation (half-life time ca. 29 hr) and accumulated in host lymph nodes and spleen to a greater extent than OX-39 (P less than 0.001). In contrast, OX-39 was retained in blood (half-life time ca. 66 hr) and was eventually sequestered in liver, lungs, and kidneys, a pattern comparable to an irrelevant IgG1 (MOPC-21). ART-18 but not OX-39 entered specifically acutely rejecting allografts (allograft:native heart activity ratio = 4.0 and 2.3, respectively, P less than 0.01). The distribution of ART-18 was IL-2R epitope but not mAb isotype specific as tissue accumulation of "hot" ART-18 was comparable in recipients conditioned with "cold" ART-18 of IgG1 or IgG2b isotype, but not in those treated with OX-39. Thus: (1) the biodistribution of anti-IL-2R mAbs is not random; the mAb "effective" in combating rejection (ART-18) penetrates preferentially host lymphoid tissues and the graft itself, whereas the biologically "ineffectual" mAb (OX-39) is retained in the circulation for prolonged periods; (ii) the epitope of IL-2R defined by the mAb is critical; a mAb may be "captured" by unrelated cells expressing a common epitope in vivo before reaching the related targets, and/or some epitopes may be more accessible than others for iv administered mAbs.

Animals↗
PubMed1989

Management of general surgical complications following cardiac transplantation.

Between February 1984 and May 1988, 55 patients underwent orthotopic cardiac transplantation at the Brigham and Women's Hospital, Boston, Mass. Basic immunosuppression was accomplished with steroid and cyclosporine therapies. Twelve patients suffered 14 major complications, including perforated ulcer in 3 patients; pancreatitis in 3 patients; pneumatosis coli in 2 patients; and cholecystitis, colonic necrosis, appendicitis, incarcerated umbilical hernia, pancreatic abscess, and toxic epidermal necrolysis in 1 patient each. Aggressive management of the patients included laparotomy in all but 2 patients with mild pancreatitis and the patient with toxic epidermal necrolysis, who was treated as a patient with a severe burn. In all of the patients, there was a resolution of these complications, except in one 59-year-old man with fatal hemorrhagic pancreatitis. Eleven of the 14 complications occurred during the initial hospitalization. The fatal case of pancreatitis was 1 of 5 (9%) operative mortalities in the entire series. Fifty operative survivors have been followed up for an average of 19 months, with four late deaths (8%) related to rejection. The actuarial probability of survival in patients discharged from the hospital was 90% at 12, 24, and 48 months.

Adolescent↗
PubMed1989

Current stage of interleukin 2 receptor targeted therapy.

The overview summarizes a new and selective form of immunosuppressive therapy by using anti-Interleukin-2 receptor monoclonal antibodies, which may soon become an important form of recipient treatment in organ/tissue transplantation or/and of patient treatment with auto-immune diseases.

Animals↗
PubMed1989

Agonistic and antagonistic interactions of anti-interleukin 2 receptor monoclonal antibodies in rat recipients of cardiac allografts.

A panel of five mouse mAbs recognizing 4 distinct epitopes (R1-4) of the rat 55kD IL-2R molecule were tested for their influence on acute rejection (8 days) of (LEWxBN)F1 cardiac allografts in LEW hosts. IL-2R1 targeted therapy with ART-18 (IgG1, inhibits IL-2-dependent responses) prolonged graft survival to ca.21 days. IL-2R2 is recognized by ART-65 and ART-75, mAbs that do not inhibit T cell growth. Treatment with ART-65 (IgG1) but not ART-75 (IgG2a) abrogated acute rejection (ca. 16 days and 9 days, respectively). ART-35, an anti-IL-2R3 mAb (IgG1, does not inhibit T cell function) extended graft survival marginally to ca. 12 days. Finally, therapy with OX-39, (anti-R4 IgG1 mAb, inhibits IL-2 binding, but not IL-2-driven growth) was completely ineffectual. Simultaneous targeting of two IL-2R epitopes increased the therapeutic index synergistically (ART-18 [R1] + ART-65 [R2]--60% permanent graft acceptance), additively (ART-75 [R1] + ART-35 [R3]--graft survival ca. 18 days), or did not improve further graft survival at all (ART-18 [R1] + OX-39 [R4]--graft survival ca. 18 days). Thus, the cellular targeting patterns and isotype of mAbs are crucial: (1) targeting at functionally distinct epitopes controls rejection most effectively; (2) IgG1 and IgG2b mAbs are more influential in vivo than IgG2a, data supported by the studies employing the family of ART-18 isotype switch variants. Treatment with anti-IL-2R mAb did not depress Ts activity as tested both in vitro and in vivo. Sparing of putative Ts by mAb is also shown by thymectomy of graft recipients before or during ART-18 therapy, which shortened graft survival to 13-15 days; thymectomy after ART-18 therapy did not influence graft survival. However, infusion of IFN-gamma recreated classic acute rejection within 10 days in otherwise longstanding cardiac allografts in ART-18 treated hosts. Upregulation of MHC class II antigen and IL-2R expression seems to be primarily responsible for this striking biological effect of IFN-gamma in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Differential IL-2 receptor expression in renal allograft recipients treated with an anti-IL-2-receptor antibody.

Patients were entered into a randomized trial of prophylaxis for renal allograft rejection by the administration of an anti-human IL-2 receptor antibody, anti-Tac, during the first ten days posttransplant. Interleukin-2 receptor (IL-2 R) expression was measured using two anti-IL-2 R monoclonal antibodies (moAbs), anti-Tac and 1HT4-4H3. These two antibodies recognize closely spaced epitopes on the 55 kD chain of the IL-2 R. IL-2 R expression was examined on peripheral blood small lymphocytes in three groups of patients who received: (A) cyclosporine CsA and prednisone for baseline immunosuppression (n = 9); (B) anti-Tac with CsA and prednisone as baseline immunosuppression (n = 12); and (C) anti-Tac with azathioprine and prednisone as baseline immunosuppression (n = 5). We found that large numbers of T cells express IL-2 receptors despite the presence of anti-Tac (average of IL-2 R-positive cells at day of peak IL-2 R expression 56.0 +/- 20.8% in group A, 65.2 +/- 26.6% in group B, 21.0 +/- 7.4% in group C). IL-2 R expression did not correlate with clinical activity, and the presence or accessibility of epitopes on the same 55 kD chain varied dramatically from patient to patient.

Antibodies, Monoclonal↗
PubMed1989

Lymphocyte migration patterns in organ allograft recipients.

A central tenet of immunology is the observation, made 30 years ago, that lymphocytes recirculate continuously between peripheral blood and lymphoid tissues. In recent years, the subject of lymphocyte migration, both under physiological conditions and in states of alloresponsiveness, has become more enigmatic. It lies outside most current topics of immunological investigations, labelling and tracing techniques are problematic, and many experimental findings are phenomenological and difficult to interpret. Indeed, our overall knowledge of the functional differences between the various host lymphoid compartments and their constituent cell populations remains rudimentary. However, as understanding increases regarding the host immunological events responding to an antigenic stimulus such as a graft, with growing definition of the distinctive and interconnecting roles of lymphocyte subpopulations and their products acting on each other to produce graft destruction, the conceptual importance of lymphocyte migration again is becoming obvious. This role includes many facets of immunity such as the effects of antigen specificity, immunologic memory, differential behavior of recirculating or sessile populations, and local and systemic contact between antigen and effector cells. It has become evident that lymphocytes migrate in a non-random and highly dynamic fashion determined by a range of specific and non-specific factors; in the setting of organ transplantation, patterns are profoundly affected by the interrelated cellular and humoral components of the immunological cascade which may lead either to graft rejection or to its prolongation in untreated and immunologically modified recipients, respectively. Thus, the traffic of lymphocytes throughout host lymphoid and non-lymphoid compartments and their activity within these compartments should be considered an integral part of the host immunomodulation triggered by transplantation of histoincompatible tissue. Gradual filling of the gaps in our current knowledge on the mechanistic aspects of this phenomenon will not only contribute to basic science itself, but also should lead to the development of innovative therapeutic approaches to treat graft rejection.

Animals↗