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K J Lafferty

Publications and source records attributed to K J Lafferty.

At least 37 records · Page 2Linked to original sources
PubMed1993

Altered cytokine activity in adjuvant inhibition of autoimmune diabetes.

The destructive insulitis that develops in disease-prone NOD mice is characterized by a high frequency of IFN-gamma-producing cells in the lesion. Complete Freund's adjuvant (CFA) challenge of young, disease-prone animals inhibits the development of diabetes but does not alter the frequency with which pancreatic insulitis develops. However, the non-destructive lesions that develop in syngeneic islets transplanted to the kidney capsule of NOD mice following CFA therapy differ in cytokine production from the destructive lesions that develop in control animals transplanted with NOD islets. Non-destructive lesions are characterized by a high frequency of IL4-producing cells and a relatively low frequency of IFN-gamma-producing cells.

Animals↗
PubMed1993

Establishment of islet-specific T-cell lines and clones from islet isografts placed in spontaneously diabetic NOD mice.

One impediment to detailed characterization of islet-specific T cells from the NOD mouse model of diabetes is the difficulty encountered in isolation of such cells. This report describes a method that allows routine isolation of relatively large numbers of T cells highly enriched for reactivity toward islet antigens. The method involves renal subcapsular transplantation of spontaneously diabetic NOD mice with NOD islets. These grafts are rapidly destroyed in a tissue-specific manner and this destruction is accompanied by lymphocytic infiltration. Here we demonstrate that the islet graft infiltrates are an excellent source of islet-specific T cells and that islet-specific T-cell lines and clones can be established from these cells. Islet-specific T-cell clones isolated from a T-cell line established from the islet graft infiltrates were capable of adoptive transfer of diabetes to NOD/LtSz-scid recipients.

Animals↗
PubMed1993

The maintenance of self-tolerance.

Two signal models for lymphocyte activation build on the Talmage/Burnet concept that receptor diversity is generated within the immune system by a random process, and that individual lymphocytes carry a single receptor on their surface that determines their specificity. Such models cannot use a concept of signal one anergy (or deletion) to explain the maintenance of self-tolerance in terms of the Bretscher/Cohn theory if they abandon the concept of associative recognition.

Allergy and Immunology↗
PubMed1992

Enrichment of beta cells from the human fetal pancreas by fluorescence activated cell sorting with a new monoclonal antibody.

The aim of this study was to produce an antibody reactive to the surface of endocrine pancreatic cells and use this antibody for the purification of endocrine cells from the human fetal pancreas by fluorescence activated cell sorting. We describe such an antibody, called N1, reacting with the surface and cytoplasm of endocrine cells in the adult and fetal human pancreas (12 to 18 weeks gestational age). While unreactive to exocrine and mesenchymal cells, it was not specific for endocrine cells, as evidenced by its staining pattern in tissues other than pancreas. Almost 40% of the N1-positive pancreatic cells contained either insulin, glucagon or somatostatin. Conversely, more than 90% of each of the hormone-containing cells was N1 positive. An additional 40% of N1-positive cells, not containing other pancreatic hormones, was shown to contain islet amyloid polypeptide, synaptophysin, chromogranin, tyrosine hydroxylase or CA812. A two-step collagenase digestion protocol yielded 1.29 +/- 0.17 x 10(5) cells per mg pancreatic tissue. After Percoll gradient centrifugation, the suspension contained 15.6 +/- 5.7% (n = 25, mean +/- SD) cells reactive with N1. By fluorescence activated cell sorting using the antibody N1, the single-cell suspension was enriched from 3.0 +/- 1.4% to 16.2 +/- 4.8% (n = 10, p less than 0.01) Beta cells. Alpha and Delta cells were also enriched significantly by this procedure. The percentage of N1-positive cells increased from 17 +/- 4% to 83 +/- 6%. This preparation enriched for endocrine cells allows future studies on possible endocrine precursor cells.

Abortion, Spontaneous↗
PubMed1992

Detection of cell-mediated immunity in type I diabetes mellitus.

Type I insulin dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, 'autoimmune' islet damage. Antibody testing is extensively used to define and follow the pre-diabetic population. However, the assay for cell mediated immunity (CMI) should be more predictive of impending disease. This report shows that it is possible to detect human islet reactive CMI in the IDDM patient. Groups of athymic CD-1 nu/nu mice were injected intraperitoneally with either mononuclear blood cells (MBCs) or plasma from 10 newly diagnosed Type I diabetic patients and 10 normal control subjects. Both glycemic control and histopathology were used to assay islet specific CMI in diabetic individuals. None of the injected mice showed any impairment of glycemic control. However, MBCs from six of 10 diabetic patients, but from none of the 10 normal subjects, induced significant mononuclear cell infiltrate in the pancreas of the recipient mice (P = 0.005). The infiltrate was focused on the islet tissue and no damage was seen in control tissues. No histological abnormalities were observed when plasma was transferred. We conclude that cellular reactivity seen in this model is tissue specific and disease associated. Our findings provide evidence that CMI to human islet tissue can be detected in IDDM patients.

Adolescent↗
PubMed1992

Facilitation of specific tolerance induction in adult mice by RS-61443.

RS-61443 is an immunosuppressive agent that facilitates pancreatic islet allograft acceptance in two mouse strain combinations (BALB/c----CBA and C57Bl/6J----BALB/c). A remarkable feature of this agent is its ability to facilitate long-term graft acceptance after a short (30 days) period of treatment; following withdrawal of the agent 40-70% of islet allografts are maintained for an indefinite period. This long-term graft acceptance has been shown to result from specific tolerance induction in the recipient animal. The state of specific tolerance is an active rather than a passive form of tolerance, such as clonal deletion or anergy. Active tolerance induction is cyclosporine-sensitive, although cyclosporine enhances graft acceptance when used in combination therapy with RS-61443, this agent inhibits tolerance development under the influence of RS-61443.

Animals↗
PubMed1992

Evidence that tolerance to cultured thyroid allografts is an active immunological process. Protection of third-party grafts bearing new antigens when associated with tolerogenic antigens.

We studied the tolerance phenomenon that develops in long-term recipients of cultured thyroid allografts. Allogeneic mouse thyroids were cultured under hyperbaric oxygen or acidic conditions and then transplanted beneath the kidney capsule of C57BL/6 recipients. Donors differed from the recipients in minor antigens alone, major histocompatibility complex antigens alone, or both. At 35-77 weeks after the first cultured graft, recipients received two more cultured grafts under the capsule of the opposite kidney and were immunized with donor spleen cells (SC). At 5 weeks after the second transplantation, we observed that whereas second grafts carrying new antigens alone were rejected, second grafts carrying new antigens in association with antigens in the first graft were significantly protected. In another set of experiments, normal mice became tolerant to cultured allografts after 2 weeks in parabiosis with tolerant individuals. Tolerant mice showed reduced specific in vivo and in vitro cytotoxic T lymphocyte responses. However, the frequency of CTL precursors of tolerant mice was the same as in normal mice. The reduced in vitro CTL responses were restored to normal levels by the addition of a lymphokine rich medium. Also, we observed that the injection of specifically activated immune SC caused the rejection of cultured allografts in normal but not in tolerant recipients. We conclude that the tolerance that develops in recipients of cultured allografts is an active immunological process that affects the activation and effector function of CTL.

Animals↗
PubMed1992

CD8 T cells are not required for islet destruction induced by a CD4+ islet-specific T-cell clone.

A panel of CD4+ T-cell clones has been isolated from the spleen and lymph nodes of diabetic NOD mice. These clones have been shown to be islet-specific both in vivo and in vitro. One of the clones, BDC-6.9, initiates extensive damage to islet tissue when placed adjacent to an NOD islet graft that has been used to reverse diabetes in (CBA x NOD)F1 recipients or when injected intraperitoneally into such animals. In this study, we show that BDC-6.9 T cells can initiate islet destruction in the absence of detectable CD8 T cells either in the periphery or in the lesion that develops after the transfer of the cloned islet-reactive T cells.

Animals↗
PubMed1991

The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice.

Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response.

Animals↗