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K J Lafferty

Publications and source records attributed to K J Lafferty.

At least 73 records · Page 4Linked to original sources
PubMed1987

Cyclosporine-induced tolerance requires antigens capable of initiating an immune response.

We studied two example where indefinite graft survival could be obtained in rats. In the first, strain DA hearts were permanently accepted in allogeneic PVG rats if the recipients were treated for at least 7 consecutive days with cyclosporine A (CsA) after transplantation. In the second, DA pancreatic islets were permanently accepted in PVG rats if the islets were cultured in vitro for 14 days in high oxygen. When cultured islet-grafted PVG rats were injected with lymphocytes from other PVG rats previously sensitized to DA alloantigens, the islet grafts were destroyed within 14 days. By contrast, it was difficult to cause the DA heart allografts to cease beating with the same adoptive transfer protocol; approximately two-thirds of the heart-grafted animals maintained their grafts. This difference was not due to the CsA as cultured islets transplanted in the presence of CsA were still susceptible to rejection by sensitized lymphocytes. However, islets that had not been cultured in high oxygen prior to transplantation and that were maintained with CsA were not rejected after the injection of sensitized lymphocytes. These results suggest that CsA can most readily induce a state of tolerance when the graft is capable of initiating an immune response.

Animals↗
PubMed1987

A quantitative analysis of antigen-triggered lymphokine production by activated T cells.

We have developed a theoretical model to describe the triggering of lymphokine release from antigen-specific, activated T (T') cells, and we have used this model to define parameters that regulate this interaction. Under assay conditions of T' cell excess, the efficiency of triggering is a function of the target cell type. When various H-2k-bearing target cells were used to trigger B10.AQR T' cells activated against B10.A cells (anti-Kk), a hierarchy of triggering efficiency was observed with B10.A Con A blasts greater than R1.1 tumor cells greater than B10.A spleen cells greater than B10.A lymph node cells. There was a 10-fold difference in triggering efficiency between Con A blasts and lymph node cells. A similar pattern of reactivity was observed for various H-2d-bearing target cells used to trigger CBA T' cells specific for BALB/c antigens (anti-H-2d). Under assay conditions of T' cell excess, the order of reaction, i.e., the number of target cells per T' cell required to trigger lymphokine release, remained constant for the different target cell types. However, the order of reaction can vary with conditions of T cell activation. CBA T' cells activated against BALB/c spleen cells exhibited pseudo-first-order reactivity when triggered for lymphokine release with P815 target cells, whereas CBA T' cells activated against UV-irradiated P815 cells exhibited pseudo-second-order reactivity when triggered by the same tumor cells. Thus, T cells with the same apparent specificity can be qualitatively different in their reactivity with antigen. Under assay conditions of target cell excess, our analysis indicated that no T-T interaction was involved in the triggering reaction. Finally, our analysis was applied to study the nature of cross-reactivity. The results indicated that the triggering of lymphokine elicited by a cross-reactive antigen was due to the reactivity of a discrete subset of T' cells.

Animals↗
PubMed1987

Blocking of delivery of the antigen-mediated signal to the nucleus of T cells by cyclosporine.

Cyclosporine (CsA) inhibits release of interleukin 2 (IL-2) and hemopoietic growth activities such as interleukin 3 (IL-3) from major histocompatibility complex (MHC)-antigen-activated T cells. Production of both lymphokines appears to be coordinately regulated; the antigen dose response, T cell dose response, and time course of lymphokine appearance are similar. The triggering of lymphokine production by these cells is solely dependent on T cell-target cell interaction, as the T cell dose response curve indicates that no cooperation occurs between T cells, and any metabolic contribution by the target cell was eliminated by ultraviolet irradiation. This interaction triggers the transcription of lymphokine-encoding mRNA. The process of lymphokine release can be divided into 4 steps: Antigen binds to the T cell; a signal is transferred to the cell nucleus; transcription of lymphokine-encoding mRNA occurs; and intact lymphokine is synthesized and secreted. CsA inhibits antigen triggered lymphokine production. However, it does not inhibit lymphokine release from the constitutively producing tumor cell lines WEHI-3 (which releases IL-3) and MLA 144 (which produces IL-2). Thus CsA has no effects on the lymphokine secretion process or any direct action upon lymphokine-coding mRNA. CsA does not affect antigen recognition during cell-mediated cytotoxicity. Therefore, CsA acts after antigen binding and before transcription of lymphokine-encoding mRNA. That is CsA blocks the transmission of the antigen signal. This information is used to show that this CsA-sensitive signal is required continuously to maintain the T cell in a lymphokine-secreting state.

Animals↗
PubMed1987

Autoimmune diabetes in NOD mouse is L3T4 T-lymphocyte dependent.

Cultured BALB/c islets fail to function when transplanted into diabetic nonobese diabetic (NOD) mice; such grafted tissue is rapidly destroyed by disease recurrence. The cellular requirements for this graft damage are unclear. This study was designed to investigate the role of the L3T4+ T-lymphocyte subset in disease recurrence in the NOD mouse. L3T4+ T-lymphocytes were depleted by the in vivo administration of the L3T4-specific monoclonal antibody GK1.5. This treatment reduced the level of L3T4+ T-lymphocytes from an initial 43% of the peripheral blood lymphocytes to less than 4%. L3T4 levels remained at this low level for approximately 2 wk after withdrawal of GK1.5 treatment, after which the L3T4 levels slowly began to increase in the periphery. Grafting of cultured BALB/c islet tissue into GK1.5-treated diabetic NOD mice resulted in a rapid return to normoglycemia that persisted for 2-4 wk. The gradual return to the hyperglycemic condition roughly correlated with the reappearance of L3T4+ T-lymphocytes in the peripheral circulation. From these findings we conclude that the disease process in the NOD mouse is L3T4 T-lymphocyte dependent.

Animals↗
PubMed1986

The allograft response.

The allograft response is a response by host T lymphocytes reacting to transplantation antigens that are carried on allogeneic lymphoreticuler cells. In vivo this response usually leads to graft rejection. It is possible to circumvent this response by the elimination of the lymphoreticular cells from the grafts prior to transplantation. The paradox of the strong response to transplantation antigen on lymphoreticular cells and the weak response to the same antigen on graft parenchymal cells can be explained by the signaling requirements for T lymphocyte activation.

Animals↗
PubMed1986

A comparative study of transplant sites for endocrine tissue transplantation in the pig.

Thyroid and thymus tissue autografts were used to examine the suitability of different transplant sites in the pig for endocrine tissue transplantation. The omental pouch, gall bladder fossa and renal subcapsular space showed optimal implantation, preservation and vascularisation of graft tissue. Marked dissemination of graft tissue was observed at intramuscular sites and graft viability at subcutaneous sites in the ear was poor. The omental pouch represents a potentially suitable site for pancreatic islet tissue transplantation studies in the pig.

Animals↗
PubMed1986

Induction and management of diabetes mellitus in the pig.

Insulin-dependent diabetes mellitus was induced in the pig by pancreatectomy or by administration of intravenous streptozotocin (150 mg/kg). High post-operative morbidity and mortality in the pancreatectomised animals made this method of inducing diabetes unsuitable for animals to be used in long term studies. By contrast, the good clinical state of animals after streptozotocin and the permanence of their diabetes indicated that these animals were suitable for long term studies such as those involving transplantation of pancreatic islet tissue. Techniques designed to facilitate the assessment and management of these animals included placement of an indwelling jugular venous catheter to enable blood samples to be obtained for metabolic studies, denervation of an area on the flank of the animal to enable insulin administration with minimum discomfort and denervation of an ear to enable blood samples to be obtained from the animal for glucose estimation in long term studies.

Animals↗
PubMed1986

Islet allografts are destroyed by disease occurrence in the spontaneously diabetic BB rat.

Transplantation of cultured islet and pituitary tissue from PVG (RT1c) donors to major histocompatibility complex-incompatible BB/D recipients (RT1u) results in tissue-specific destruction of the grafted islets but not of the pituitary. We interpret this response as disease occurrence in the MHC-incompatible islet graft. Islet damage is associated with eosinophil and mast cell accumulation in and around the grafted tissue. Antibody deposition is also present in tissues of the BB rat. This is suggestive of an antibody-mediated allergic reaction.

Animals↗
PubMed1986

Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice.

Nonobese diabetic (NOD) mice get spontaneous diabetes with clinical and pathological manifestations similar to those seen in human type I diabetes. NOD mice will destroy transplants of treated allogeneic islet tissue by a recurrence of the disease process that destroyed the original islet tissue. This may be prevented by treatment of the animals with combined desferrioxamine and nicotinamide. Transplanted animals become normoglycemic and remain so for the duration of the treatment. This suggests that oxygen-derived free radicals may be involved in islet damage in spontaneous diabetes.

Animals↗
PubMed1986

Reversal of diabetes in outbred mice by islet allotransplantation.

The combination of donor pretreatment with cyclophosphamide, organ culture in 95% O2:5% CO2 for 7-10 days, and short-term immunosuppression of recipients with cyclosporin A (CsA) were necessary to obtain 100% survival of single-cluster BALB/c islet allografts in outbred mice. In vivo and in vitro pretreatment of the donor tissue alone resulted in the acceptance of 45% of the islet allografts in nonimmunosuppressed outbred mice. CsA treatment of recipients alone yielded 40% survival of the untreated allografts. CsA treatment played an important role in maintaining the capacity of islet allografts to function in outbred mice. During CsA treatment, 88% of streptozocin-treated mice showed graft-dependent reversal of diabetes; the remainder showed no evidence of graft function, and CsA treatment failed to prevent acute graft rejection. After withdrawal of CsA immunosuppression, 38% of this total group remained normoglycemic. These findings suggest that modulation of both donor-tissue immunogenicity and recipient responsiveness will be required for successful pancreatic islet transplantation in diabetic humans.

Animals↗
PubMed1986

Desferrioxamine treatment prevents chronic islet allograft damage.

BALB/cByJ islet allografts are acutely rejected when transplanted into allogeneic mice (CBA/J). Culture of the tissue for 7 days in 95% O2 before grafting is a suboptimal treatment for the reduction of immunogenicity in this strain combination. Approximately half the animals reject these transplants in a chronic fashion. Chronic islet rejection differs from acute rejection of uncultured allogeneic islets. During chronic rejection, beta cells within the transplanted tissue degranulate but remain intact when the animal returns to the diabetic condition. Acute islet rejection is characterized by the destruction of beta cells that remain heavily granulated as long as they remain intact. We examined the effect of the iron chelating agent, desferrioxamine, on chronic islet allograft damage. Desferrioxamine inhibited chronic islet allograft damage but did not influence the process of rejection of uncultured islet tissue. This effect of desferrioxamine could not be attributed to a direct immunosuppressive effect of this agent.

Animals↗
PubMed1986

Prevention of rejection by treatment of the graft: an overview.

Two signals are required for T cell activation, and because of this transplantation antigen, of itself, is not the major barrier to grafting. The major stimulus for the rejection response come from active antigen presentation by donor APC's. It is possible to reduce allograft immunogenicity by removal of these cells from the graft prior to transplantation. This procedure has been shown to be effective in the case of thyroid, parathyroid, and islet cell transplantation in animals and in the case of parathyroid grafting in man. The cultured graft is in a metastable state in the immediate post-transplantation phase; such grafts are rejected by either active or passive immunization of the host animal. With the passage of time the metastable graft moves into a stable relationship with the host. This change is the result of tolerance induction in the adult animal. The fact that allografting can be carried out without a requirement for recipient immunosuppression suggests that the helper pathway involving processing of graft antigen and presentation on host APC's, is relatively inefficient in vivo. Experimentally, lymphokine provided by T cell triggering in the region of the metastable graft does not lead to the generation of systemic immunity, suggesting that there are much more stringent requirements for the expression of T helper function in vivo than in vitro.

Animals↗