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Biomedical subjects

R H Lord

Publications and source records attributed to R H Lord.

30 records · Page 2Linked to original sources
PubMed1987

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.

Animals↗
PubMed1987

Identification of IL 2R+ T cells and macrophages within rejecting rat cardiac allografts, and comparison of the effects of treatment with anti-IL 2R monoclonal antibody or cyclosporin.

Monoclonal antibodies to lymphokine-induced activation antigens of lymphocytes and macrophages were used to analyze the intragraft events occurring during acute rejection of rat heterotopic cardiac allografts. The cells present during untreated rejection were then compared with those present in situ after immunosuppression with the mouse anti-rat IL 2 receptor (anti-IL 2R) monoclonal antibody ART-18 or cyclosporin (CsA). Untreated rats rejected their grafts within 7 days, whereas rats receiving 10 days of i.v. ART-18 antibody therapy showed graft prolongation to more than 21 days, and rats receiving CsA for 7 days maintained their grafts indefinitely. Untreated rejection was associated with an influx of T (W3/13+) cells and macrophages (ED-1+, ED-2+). Activated mononuclear cells (IL 2R+) were identified within rejecting grafts from day 2, and their numbers peaked on days 4 to 6 when 15 to 20% of infiltrating leukocytes were IL 2R+. Double labeling studies of IL 2R+ cells present at day 6 showed surprisingly that both T cells and macrophages expressed IL 2R. In particular, although 55.8 +/- 6.9% (mean +/- SD) of IL 2R+ cells expressed the pan-T cell antigen 3/13, a similar proportion of IL 2R+ cells (49.8 +/- 8.2%) expressed the macrophage antigen ED-2. Conversely, both T cells and macrophage populations showed heterogeneity in their expression of IL 2R, because 39.2 +/- 12.2% of T cells and 31.0 +/- 13.4% of macrophages were IL 2R+. In addition, inflammatory macrophages at day 6 expressed the A1-3 antigen. Expression of this antigen by macrophages has previously been linked with development of macrophage procoagulant activity, and in this model intragraft inflammatory macrophages were closely associated with widespread deposits of fibrin. By comparison with untreated animals, rats treated with either ART-18 or CsA both lacked detectable IL 2R+ cells during the first 14 days post-transplantation (post-Tx), and showed significantly less cellular infiltration. However, although grafts of CsA-treated animals continued to remain IL 2R- and failed to stain with the macrophage activation marker A1-3, ART-18-treated rats showed increasing infiltration by both IL 2R+ mononuclear cells and A1-3+ macrophages, as well as increasing perivascular and interstitial fibrin deposition, prior to rejection by day 22. These studies document the presence of small number of activated intragraft T cells and macrophages during rat cardiac rejection, and show how CsA, and to a lesser extent anti-IL 2R therapy, inhibit this in situ activation and prolong graft survival. (ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts.

(LEW X BN)F1 cardiac allografts are rejected within 8 days in unmodified LEW rats. ART18, a mouse anti-rat IgG1 monoclonal antibody which binds specifically in vitro to the interleukin 2 receptor (IL 2R) molecule expressed primarily on activated T cells, prolongs allograft survival in a dose-dependent fashion to ca. 3 weeks (p less than 0.001) after being administered for 10 days after transplantation. This effect was related to the specificity of the antibody for IL 2R, as therapy with ART62 (a monoclonal antibody recognizing MHC class I antigen but not binding the rat IL 2R) was ineffectual. Suppressor activity was detected in spleen cells of ART18-treated grafted hosts: in vivo, splenic T suppressor/cytotoxic fraction adoptively transferred into normal LEW improved donor-specific but not third-party test graft survival (17 days, vs. 8 days, respectively, p less than 0.001); in vitro, mixed lymphocyte reaction was profoundly but nonspecifically inhibited (less than 5% of test mixed lymphocyte reaction, p less than 0.001 as compared to acutely rejecting controls). In contrast, splenic T helper (Th) cells from ART18-treated hosts were functionally depressed, as noted by their passive transfer into immunologically anergic B recipients of cardiac allografts (rejection in ca. 40 days, vs. ca. 13 days after transfer of Th from specifically sensitized rats). ART18 treatment also resulted in diminished elaboration of IL 2 as compared to normal (p less than 0.005) or acutely rejecting hosts (p less than 0.001); however, a remarkable increase in the production of IL 3 occurred (p less than 0.001). These results demonstrate that IL 2R-targeted therapy of immunocompetent graft recipients produces a selective immune defect in which donor-specific T suppressor cells are spared, but Th cells attenuated or destroyed. Decreased elaboration of IL2 concomitantly augments the release of IL 3, a lymphokine which might play a role in suppressor effect in vivo. In addition, IL 2R-targeted therapy of the immunodeficient graft recipients abrogates the capacity of alloactivated T cells to re-establish acute immune responsiveness.

Animals↗
PubMedDate not supplied

The CSAT methamphetamine treatment program: research design accommodations for "real world" application.

The Methamphetamine Treatment Program (MTP), funded by the Center for Substance Abuse Treatment, has the objectives of implementing the Matrix outpatient model and evaluating that model in comparison to the existing community "treatments as usual." Seven organizations in three western states (California, Montana, and Hawaii) were selected to participate in this randomized, controlled, multisite project in what constitutes the largest trial to date of treatment for methamphetamine (MA) dependence. One hundred fifty MA-dependent patients recruited at each site are randomly assigned to receive either the Matrix model, a manualized program of intensive outpatient treatment, or the site's standard treatment, "treatment as usual." Participants are evaluated at admission, weekly during treatment, at the time of scheduled discharge, and at six and 12 months after admission. Dependent measures assess changes in drug use, HIV risk behaviors, quality of life, and patient satisfaction. Cost analyses to quantify treatment costs and determine the association between costs and clinical outcomes will be conducted. A number of adjustments in the original study design have been necessitated by the realities of community sites' strengths and limitations. Experiences from this multisite project will also provide a model for other efforts to transfer research-based treatments into community settings. This article describes the main aims of the project, the background and rationale for the study design, a brief description of the research plan, and methods implemented to protect the integrity of the science.

Central Nervous System Stimulants↗
PubMedDate not supplied

Methamphetamine abuse: issues for special populations.

Methamphetamine (MA) abuse has been a problem in the western United States for decades. However, recently the incidence of MA abuse has risen to epidemic levels in some regions and among particular subgroups of the population. Recognizing the need to develop effective treatments for MA dependence, the Center for Substance Abuse Treatment (CSAT) established a multisite Methamphetamine Treatment Program (MTP) that compares the Matrix Model treatment program for MA to the treatments as usual at seven community-based clinics in California, Montana and Hawaii. Examination of the clients receiving services though this project provides an opportunity to explore particular issues of diverse special populations who are impacted by the problem of MA dependence. These groups include rural Americans, Native Americans, Hawaiians, gay and bisexual males and drug court participants. Specifically, this article examines cultural, geographic and situational barriers to accessing and completing treatment and presents strategies that have been used to overcome these barriers.

Bisexuality↗
PubMedDate not supplied

A descriptive analysis of participant characteristics and patterns of substance use in the CSAT methamphetamine treatment project: the first six months.

The CSAT Methamphetamine Treatment Project (MTP) is a multisite study with a two-fold purpose: to assess the feasibility and outcomes generated by a technology transfer of the Matrix treatment model for methamphetamine (MA) abuse into several community-based treatment programs, and specifically to compare outcomes of treatment as usual at each site with outcomes of the Matrix model, as implemented in each site. The study comprises seven sites, geographically situated in Hawaii, Northern and Southern California, and Montana. This article presents a demographic description of the cohort, and describes patterns of drug use, abuse, and related problems among the 169 participants recruited in the first six months of the study, from April through September 1999. Specific analyses presented include: demographic composition of the sample with respect to gender, age, ethnicity, education completed, employment status, and income; primary drug used, and mean percent of days using various drugs including MA, alcohol, and marijuana; and percent of sample reporting various routes of drug administration. Mean baseline Addiction Severity Index composite scores are presented that describe medical, employment, alcohol, drug, legal, family/social, and psychiatric status for the sample. Also presented here are comparisons of this preliminary population to other populations reported in the literature. This early subset of MTP participants is similar to other methamphetamine-abusing populations described in the literature in age, years of education, income, and mean years of use. However, because of its multisite structure and the locations of its constituent sites, the MTP population has greater variation in ethnic makeup than do populations from other studies, offering an opportunity to provide useful new information about drug use patterns and treatment responses in populations not previously studied.

Adult↗