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K J Lafferty

Publications and source records attributed to K J Lafferty.

At least 55 records · Page 3Linked to original sources
PubMed1990

In vivo activity of an islet-reactive T-cell clone.

BDC-6.9 is a CD4-positive T-cell clone, specific for NOD islets, which was isolated from the spleen and lymph nodes of a diabetic NOD mouse. The cells were transplanted in a blood clot adjacent to established NOD islet grafts in diabetic (CBA X NOD)F1 recipients. The BDC-6.9 cells initiated extensive damage to the islet grafts, while a non-islet specific clone transplanted adjacent to grafted islets caused no noticeable damage. In addition, the BDC-6.9 cells initiated similar destruction when injected intraperitoneally, suggesting that they may have some migratory capacity. By introducing these islet-reactive cells into the (CBA X NOD)F1, a non-diabetes prone environment, we hope to clarify the role of the islet-specific CD4 cell as related to islet destruction in vivo.

Animals↗
PubMed1990

Role of lymphokine in islet allograft rejection.

Primed CD8 T cells transfer allograft immunity to an established islet allograft. However, the process is inhibited by cyclosporine, suggesting that lymphokine production is required for islet graft rejection. The alloreactive T cell clone L3 will transfer allograft immunity, and this process is also sensitive to CsA. The L3 clone produces gamma-interferon and tumor necrosis factor but not IL-2 and IL-3. It follows therefore that the latter lymphokines are not required for the rejection process. Pretreatment of islet tissue with gamma-IFN prior to grafting increases the density of the class I major histocompatibility complex antigen on the islet tissue, and CsA can no longer block the destruction of this MHC-induced tissue by primed alloreactive T cells. We conclude that gamma-IFN, and possibly TNF, act cooperatively with cytotoxic function in the process of islet allograft rejection.

Animals↗
PubMed1989

A quantitative analysis of lymphokine release from activated T cells. Evidence for a novel form of T-T collaboration in vitro.

We previously developed a simple mathematical model describing Ag-triggered lymphokine release from activated T cells. Previous test of this model revealed qualitative differences in the antigenic requirement for lymphokine release between activated T cell populations with the same apparent specificity when activated under different conditions. We now have found a case where class I MHC-reactive T cells (class I T cells) can modulate the nature of Ag-triggered lymphokine release from class II MHC-reactive T cells (class II T cells). Two significant requirements for this modulation event are: 1) Linked recognition/presentation of class I and class II Ag; that is, class I and class II MHC alloantigens must be presented on the same APC, and 2) active participation of the APC in this process; metabolic inactivation of the APC abrogates the class I T cell modulation of the class II activated T cell. These results suggest a novel form of T-T collaboration that involves the active participation of the APC, and provides evidence that T cells of one MHC specificity (class I) can influence the function of T cells of another MHC specificity (class II).

Adjuvants, Immunologic↗
PubMed1989

Characterization of primary T cell subsets mediating rejection of pancreatic islet grafts.

The cellular mechanisms by which pancreatic islet grafts are rejected have not been clearly defined. In order to address the roles of CD4+ and CD8+ T cells in pancreatic islet rejection, we used an adoptive transfer model in which H-2b nude mice were reconstituted with negatively selected H-2b CD4+ or CD8+ T cell subpopulations and engrafted with fully allogeneic pancreatic islet grafts. We found that primary (unprimed) CD4+ T cells mediated the rejection of pancreatic islet grafts, whereas, primary CD8+ T cells failed to do so, even though both T cell subpopulations were competent to reject skin allografts. These data indicate that primary CD4+ T cells are necessary for rejection of allogeneic pancreatic islet grafts, whereas primary CD8+ T lymphocytes are not. Implications concerning the nature of the APC involved in the initiation of the rejection response to islet allografts and the expression of MHC Ag by pancreatic islet cells are discussed.

Animals↗
PubMed1989

In vivo administration of interleukin-1 inhibits glucose-stimulated insulin release.

Recombinant interleukin-1 beta (IL-1 beta) was administered intraperitoneally for 3 days to normal C57BL/6ByJ (B6) mice. The islets from IL-1-treated and control animals were isolated and glucose-stimulated insulin secretion studied in the perifusion system. The total islet insulin content and the ultrastructure of the islets isolated from the animals treated with IL-1 did not differ from those seen in control animals. However, glucose-stimulated insulin release was significantly impaired after 3 days of in vivo administration of IL-1, either 3 micrograms/animal/day or 0.3 micrograms/animal/day. The administration of IL-1 inhibited an acute phase of glucose-induced insulin release, whereas neither basal insulin secretion nor insulin release from 10-30 min of perifusion with glucose was impaired. There was an only partial (27%) and non-significant restoration of the insulin secretory response to glucose stimulation 4 days after discontinuation of IL-1 treatment. We conclude that IL-1 administered in vivo is capable of adversely affecting pancreatic islet response to glucose stimulation. After 3 days of administration, these changes are confined to the process of insulin release, with the islet cell morphology and total insulin content being unaffected.

Animals↗
PubMed1989

Involvement of O2 radicals in 'autoimmune' diabetes.

Spontaneous diabetes in the non-obese diabetic (NOD) mice is a CD4 T cell-dependent process. We have suggested that specific beta cell destruction results from free radical production at the site of islet inflammation; oxygen radicals are produced by activated inflammatory cells. We reported here that in vivo treatment of spontaneously diabetic NOD mice with the enzyme superoxide dismutase (2000 U for seven injections) and catalase (40,000 U for seven injections) protects islet tissue from disease recurrence following transplantation into spontaneously diabetic mice. Similar results were obtained when animals were treated with either enzyme alone. This effect was dose-dependent and little protection was observed when the dose of enzyme was reduced four-fold. These results indicate that oxygen metabolites, specially superoxide and hydrogen peroxide, are directly involved in the pathogenesis of immunology mediated diabetes.

Animals↗
PubMed1988

Effect of cyclosporine on immunologically mediated diabetes in nonobese diabetic mice.

Spontaneous diabetes in NOD mice has an immunologically mediated cause and is a T cell-dependent process. When diabetic NOD mice are grafted with cultured BALB/c islet tissue, the islet graft is destroyed by disease recurrence in the graft. Disease recurrence is a CD4 T cell-dependent process as determined by in vivo administration of anti-CD4 or anti-CD8 monoclonal antibody prior to the grafting of islet tissue. Cyclosporine functions in the early sequence of T cell activation by regulating the production of messenger RNA for lymphokines synthesis. Cyclosporine does not inhibit the synthesis of lymphokine once the lymphokine message is present in the cell. Thus, we might expect cyclosporine to be relatively inefficient as an agent for the regulation of disease recurrence following transplantation to actively diabetic recipients, and we would expect cyclosporine to be more effective when administered before the onset of the disease. Low-dose cyclosporine treatment can prevent development of the disease when the drug is administered before the onset of disease. Data presented here show that cyclosporine is ineffective in controlling disease recurrence in the islet graft transplanted to actively diabetic animals. Also, when we eliminate CD4 T cells from the diseased animals and graft islet tissue prior to the administration of cyclosporine, we are unable to maintain a graft with low-dose cyclosporine therapy. This result leads us to conclude that, although anti-CD4 treatment controls the expression of the disease process and allows the survival and function of the islet graft, this treatment does not return diseased animals to the prediabetic condition in which the development of diabetes can be controlled by low-dose cyclosporine therapy.

Animals↗
PubMed1987

Role of the L3T4+ T cell in allograft rejection.

Pancreatic islet and fetal pancreas allotransplantation has been used to examine the role of the L3T4+ T cell in allograft rejection. Tissues were grafted into recipient animals depleted of peripheral L3T4+ T cells by in vivo administration of GK1.5 (anti-L3T4) monoclonal antibody to ask the question: is there a requirement for the L3T4+ T cell in graft rejection? Data show that the requirement for the L3T4+ T cell depends on either the type of tissue transplanted or type of the antigenic disparity between donor and recipient. Data also indicate that islet allograft acceptance achieved after GK1.5 treatment of the recipient is not due to tolerance induction. We therefore conclude that the cellular requirements for allograft rejection are determined by the type of tissue transplanted and the genetic disparity between donor and recipient.

Animals↗