Biomedical subjects

M A Hardy

Publications and source records attributed to M A Hardy.

At least 73 records · Page 4Linked to original sources

PubMed1995

Transplantation tolerance to rat cardiac and islet allografts by posttransplant intrathymic inoculation of soluble alloantigens.

The search for strategies for induction of specific tolerance in adult animals that will avoid long-term host immunosuppression with its complications has led to the deliberate introduction of alloantigens (Ag) into the adult thymus. However, pretransplant intrathymic (IT) inoculation of alloantigens (Ag), which has consistently induced tolerance to vascularized and neovascularized allografts in adult rodents, has limited future clinical application. To overcome the practical limitations of pretreatment, we have examined in the Lewis-to-WF combination the effect on graft survival of either simultaneous or posttransplant IT inoculation of soluble Ag obtained from 3M KCl extracts of donor T cells in transiently rabbit antirat lymphocyte serum (ALS) immunosuppressed recipients. While IT injection of 2.0 mg soluble Ag alone on day of cardiac transplantation caused acute graft rejection, IT inoculation of 2.0 mg Ag combined with 1 ml ALS transient immunosuppression of the recipient on day 0 led to long-term graft survival (> 250 days) in 5/6 recipients. Similarly, IT injection of soluble Ag on posttransplant day 3 or day 7 combined with 1 ml ALS on day 0 relative to allografting resulted in permanent graft survival in all recipients. In contrast, intravenous injection of soluble Ag combined with ALS immunosuppression on day 0 led to acute graft rejection that paralleled the rejection seen in ALS treated controls. Third-party Brown Norway (BN) hearts were acutely rejected in similarly prepared recipients of IT-Ag, thus confirming donor specificity. The long-term unresponsive Wistar-Furth (WF) recipients challenged 100 days after cardiac transplantation with a second-set graft specifically and permanently (> 100 days) accepted the second-set donor cardiac allografts, thus demonstrating donor-specific tolerance. In similar experiments, IT inoculation of 2 mg soluble Ag combined with transient ALS immunosuppression resulted in donor-specific unresponsiveness to islets in the same rat combination of Lewis-to-WF. Our findings suggest that this new strategy of immunologic manipulation of the adult thymus offers a safe, effective, and reproducible method of inducing tolerance that may have therapeutic application in cadaveric organ transplantation.

Animals↗

PubMed1995

Tolerance induction to cardiac allografts by simultaneous or sequential intrathymic inoculation of disparate alloantigens.

Recent studies show that the adult immune system can be manipulated to accept allografts by the intrathymic (IT) inoculation of donor alloantigens (Ag). To make this model clinically applicable to cadaveric transplants, we have examined the effect of simultaneous or sequential IT injection of two disparate Ags on graft survival. In initial experiments, Wistar Furth (WF) rats received IT injections of a single or an admixture of 2 x 10(7) Lewis T cells and 2 x 10(7) BN T cells 7 days prior to cardiac transplantation. Untreated WF recipients acutely rejected single Lewis, BN, and ACI heart allografts, respectively, at times equivalent to rejection of double hearts while IT injection of single or double 2 x 10(7) Lewis and 2 x 10(7) BN T cells on day -7 also led to acute graft rejection. As expected, IT injection of donor-type resting T cells combined with 1 ml ALS recipient immunosuppression on day -7 led to donor-specific Lewis or BN permanent graft survival (> 200 days). The long-term unresponsive WF recipients challenged 100 days after cardiac transplantation with 2nd-set grafts specifically and permanently accepted 2nd-set donor cardiac allografts. IT injection of an admixture of 2 x 10(7) Lewis and 2 x 10(7) BN T-cells combined with 1 ml ALS on day -7 resulted in 100% permanent double (Lewis and BN) allograft survivals (> 150 days). Similar treatment led to acute rejection of third-party (ACI) grafts while the simultaneously transplanted Lewis hearts survived indefinitely (> 150 days). In the second group of experiments, unresponsive recipients of single (Lewis or BN) cardiac allografts were given IT inoculation of a second Ag in a sequential fashion 30 or 100 days after primary heart transplant. Unresponsive WF recipients of Lewis grafts accepted permanently (> 100 days) second BN grafts that were transplanted 30 or 100 days after primary Lewis graft and 7 days after IT injection of BN T-cells and 1 ml ALS. Similarly, unresponsive WF recipients of BN grafts accepted second Lewis grafts after IT injection of Lewis T cells combined with ALS, 30 or 100 days after primary BN grafts. To define the mechanism of peripheral tolerance in this model, we have shown that adoptive transfer of unseparated spleen cells from unresponsive recipients induces prolonged double (Lewis and BN) graft survivals (> 60 days) but not ACI grafts in sublethally irradiated (400 rads) syngeneic (WF) recipients, thus suggesting that maintenance of tolerance is, in part, dependent on suppressor/regulatory cell network.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Effects of ultraviolet-B irradiation on human LAK and NK cytotoxic activity.

In vitro ultraviolet-B (UVB) irradiation of murine and rodent bone marrow cells prevents GVHD without compromising engraftment while inducing tolerance to donor-type allografts. In anticipation of clinical trials of UVB-modified bone marrow grafts, we studied the in vitro effects of UVB irradiation (50-300 J/m2) on human natural killer and lymphokine activated killer cells since both types of cells influence the development of GVHD and graft-versus-tumor effect. Interleukin-2-activated and untreated human lymphocytes were used as effectors in a 51Cr release cytotoxic assay against various tumor cell lines as targets. NK-mediated lysis of K562 targets was decreased by UVB irradiation of the effector cells in a dose-dependent manner. FACS analysis of CD16+ and CD56+ cells 24 hr after UVB exposure showed a UVB-dose-dependent decrease in the number of cells expressing these surface markers. UVB irradiation of lymphocytes prior to activation with high-dose IL-2 resulted in a range of 20- to 89-fold decrease in LAK precursors as measured by limiting dilution analysis using the LAK-sensitive cell line HL60. In contrast, the LAK activity of lymphocytes that had been stimulated in vitro with high-dose IL-2 prior to UVB irradiation was preserved when assayed immediately after UVB modulation; however, there was a significant decrease in lytic activity (with most samples tested) when the assay was performed 24 hr after UVB exposure. It appears that the lymphocyte response to UVB modification is dose dependent, with some cell types displaying higher sensitivity to UVB irradiation than others. These findings suggest that prevention of GVHD by UVB is due, in part, to inhibition of NK activity, and may offer a new strategy to augment the graft versus leukemia effect of UVB-modified bone marrow grafts in clinical transplantation.

Bone Marrow Transplantation↗

PubMed1995

Transplantation.

Multicenter studies have not substantiated concerns regarding the nephrotoxicity of cyclosporine. Perioperative donor-specific bone marrow transplantation has been used in human organ transplantation in an effort to induce unresponsiveness to allografts.

Humans↗

PubMed1995

Donor-specific unresponsiveness to murine cardiac allografts induced by intrathymic-soluble alloantigens is dependent on alternate pathway of antigen presentation.

This study extends the finding that intrathymic (IT) inoculation of uv-B irradiated donor spleen cells (SC) or soluble alloantigens (Ag) induces peripheral tolerance to organ allografts in the rat to the murine cardiac allograft model. In our initial experiment, we showed that IT inoculation of uv-B irradiated SC combined with transient immunosuppression of the recipient with either sublethal TBI or ALS on Day -7 led to donor-specific, long-term cardiac allograft survival (> 300 days) in the completely mismatched A/J-to-C57BL/6 mice combination. To test our hypothesis that peripheral tolerance induced by IT injection of donor Ag is dependent on presentation of the foreign MHC molecule by thymic APC to T cell precursors, we examined the effect of IT injection of donor APC-free-soluble Ag inoculum obtained from 3 MKCl extracts of purified MHC class I resting T cells on cardiac allograft survival in the A/J-to-C3H mice combination. The results showed that IT injection of the optimal dose of 500 micrograms soluble Ag combined with 0.5 ml ALS on Day -7 led to donor-specific permanent graft survival (> 200 days). This finding could not be reproduced by intravenous administration of soluble Ag, thus confirming the privileged position of the thymus in tolerance induction. To further define the role of host APC in allorecognition, we studied the presentation of soluble Ag by responder APC in MLR. The results showed that primed T cells obtained from A/J skin graft-sensitized C3H T cells specifically developed alloreactivity to A/J-soluble Ag in MLR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Satisfaction with early retirement: making choices in the auto industry.

In recent decades, the expanded availability of early retirement incentive plans has allowed an increasing number of workers to retire at an age younger than normally allowed by their pension plans. On the surface, these retirement incentives appear to offer older workers more flexibility in deciding when to retire. However, the offer of early retirement incentives frequently occurs when employers are attempting to reduce employment; therefore, the opportunity for early retirement may be counterbalanced by downsizing goals that place older workers' continued employment in jeopardy. Early retirement incentive programs are thereby characterized by an unusual combination of inducement and coercion. In this study, we examined how the structure of the early retirement program shapes the way older male auto workers evaluate their retirement transitions. We conclude that the structure of the early retirement program, the timing of the retirement decision, and job security are important in framing the retirement transition and in distinguishing levels of satisfaction with the retirement experience.

Automobiles↗

PubMed1995

Prevention of cyclosporine-induced syngeneic graft-versus-host disease in bone marrow transplantation by UV-B irradiated bone marrow cells.

UV-B irradiation of allogeneic rat bone marrow cells (BMC) transplanted into lethally gamma-irradiated recipients prevents GVHD and induces stable complete hematopoietic chimerism. Cyclosporine (CsA), an effective immunosuppressive agent, causes an autoimmune syndrome termed syngeneic GVHD in syngeneic radiation chimeras following discontinuation of CsA. To understand the in vivo interactions of CsA with UV-B modulated syngeneic bone marrow transplant (BMT), as this is essential before clinical use, we studied the effects of CsA therapy in recipients of UV-B irradiated donor BMT in the rat model. Lethally irradiated (10.5 Gy) Lewis recipients of naive or UV-B irradiated syngeneic BMT (admixture of 10(8) BMC and 5 x 10(6) spleen cells) were treated with CsA (i.m. 12.5 mg/kg/day) for 30 consecutive days after BMT. The results show that all irradiated Lewis recipients of syngeneic BMT modulated with 700 J/m2 UV-B were hematologically fully reconstituted in 25-35 days and survived their normal life span. In contrast, all lethally irradiated recipients of untreated BMT that received CsA for 30 days developed lethal acute syngeneic GVHD 7-12 days after CsA withdrawal. Of interest is the finding that while higher doses of UV-B (500-700 J/m2) irradiation of BMC prior to transplantation into CsA-treated animals prevented hemopoietic reconstitution, lower doses (100-300 J/m2) allowed for hemopoietic recovery and, in addition, prevented the development of syngeneic GVHD following the discontinuation of CsA. The development of syngeneic GVHD was dependent on the presence of the thymus and did not occur in thymectomized recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995