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D H Mintz

Publications and source records attributed to D H Mintz.

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

Effect of FK 506 on spontaneous diabetes in BB rats.

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.

Animals↗
PubMed1990

Experience with islet immunoalteration in dogs: in vitro and in vivo studies.

In an attempt to prolong canine islet allograft survival, in the presence of minimal or no recipient immunosupression, two methods of islet immunoalteration were utilized prior to transplantation. With or without administration of subimmunosuppressive doses of cyclosporin A (CSA) to recipients, treatment of islets with anti-class II monoclonal antibody (moab) and complement (C) resulted in prolongation of allograft survival when treatment was combined with a culture period of 7 days. Transplantation of ultraviolet light (UV) irradiated, 24 hour cultured islets into recipients of subimmunosuppressive doses of CSA also resulted in modest prolongation of allograft survival.

Animals↗
PubMed1988

Advances in canine diabetes mellitus research: etiopathology and results of islet transplantation.

Histopathologic and immunocytochemical alterations in the pancreas of 18 dogs with spontaneous diabetes mellitus were evaluated. In 5 of 18 dogs (28%), extensive pancreatic damage appeared to be responsible for the development of diabetes mellitus. In the other 13 dogs, there was substantial reduction in the number of well-granulated beta cells, but the number of well-granulated alpha and delta cells was normal in 70% and 85% of the dogs, respectively. Also, insulitis lesions composed of infiltrating mononuclear cells, predominantly lymphocytes, were observed in 6 of 13 dogs (46%), but evidence of islet-directed humoral autoimmunity was not detected. Each pancreas had dense Ia (class II antigen) expression on ductal epithelia but not on islet endocrine cells. The importance of the insulitis lesions and class II antigen expression on ductal epithelial cells remains unclear. Of the 18 dogs, 8 received multidonor intrahepatic islet allografts. Allograft rejection was prevented by administration of cyclosporin. Five dogs were administered cyclosporin continuously. One dog with an allograft failed to sustain euglycemia at 231 days after transplantation, and one dog with fasting euglycemia died of pneumonia at 186 days after transplantation. In the other dogs, euglycemia was sustained for periods that ranged from 253 to 716 days.

Animals↗
PubMed1987

Effect of anti-Ia antibodies, culture, and cyclosporin on prolongation of canine islet allograft survival.

Evidence in rodents suggests that islet pretreatment to reduce islet immunogenicity will also require some form of immunosuppression of the recipient for islet allograft acceptance in highly reactive donor-recipient pairs. We attempted to ascertain whether outbred dogs would also require treatment of both donor islets and the recipient to prolong islet allograft survival. Untreated canine islets are uniformly rejected in 6-10 days in beagles. Tissue culture alone, at 37 degrees C for 7 days, or treatment of freshly prepared islets with anti-Ia monoclonal antibodies (MoAbs) (B1F6 + 7.2) did not prolong canine islet allograft survival. Treatment of culture-maintained canine islets with anti-Ia MoAbs plus complement resulted in prolongation of islet allograft survival for 188 and 368 days in two of seven pancreatectomized nonimmunosuppressed beagles. The administration of low doses of cyclosporin A (CsA) intramuscularly, to recipients of untreated canine islet allografts had no effect on graft survival. By contrast, six of nine CsA-treated recipients of islets that were also treated with anti-Ia MoAbs (B1F6 + 7.2) plus complement showed prolongation of graft survival. Euglycemia was sustained for 19, 34, 89, and 300 days after the CsA was discontinued (day 30) in four of these animals. Two animals had unstable grafts from the beginning that failed 23 and 29 days after transplantation. Our results indicate that simple maneuvers like short-term tissue culture at 37 degrees C and treatment of freshly isolated islets with anti-Ia MoAbs and complement are inadequate to prevent rejection in outbred pancreatectomized beagles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Human pancreatic cell surface antigens with homologous expression in liver, sweat glands, and other exocrine tissues.

We have generated two panels of monoclonal antibodies (MoAbs) that represent a unique array of immunolabeling reagents specific for diverse cell surface and intracellular antigens of ductal epithelial cells (DEC) and of acinar cells (AC) within the human pancreas. Eight of the MoAbs are specific within the pancreas for the DEC plasma membrane (PM), three for DEC intracellular antigens, seven for AC-PM, and one for AC secretory granules. The MoAbs with PM reactivities have permitted us to substantially enhance our assessment of exocrine contamination in our human islet preparations. However, we have been unable to demonstrate consistently the effectiveness of these MoAbs in complement-mediated cytotoxicity protocols designed to improve the purity of our islet preparations by exocrine cytolysis. It is possible that primary cell isolates of pancreas or epithelial organs in general may lack inherent susceptibility to complement-mediated cytolysis or, instead, that this particular panel of MoAbs lacks the appropriate characteristics needed to achieve consistent complement-mediated cytolysis. We have also begun to explore the potentially broader applicability of the anti-DEC MoAbs as immunocytochemical tools and have observed intriguing patterns of cross-reactivities in other exocrine tissues, particularly bile duct epithelial cells in the liver and functionally discrete subsets of DEC in the eccrine sweat gland and the parotid gland. These homologous antigenic patterns, by virtue of their specificities for ductal tissue, most likely reflect the molecular bases for functions common to these tissues, e.g., active ion transport and mucin secretion. In addition, the anti-DEC and the anti-AC MoAbs exhibit patterns of binding specificity for human cell lines derived from pancreatic adenocarcinoma that suggest the potential value of these MoAbs in tumor diagnosis and therapy. We believe that these panels of MoAbs will find broad utility in immunopathology and in experimental approaches to questions regarding the development, normal function, and pathogenetic mechanisms in the human pancreas and other related organs as well.

Adenocarcinoma↗
PubMed1986

Identification of Ia-bearing cells in rat, dog, pig, and human islets of Langerhans.

Cells expressing Ia-like antigens (Ia) are believed to provide the primary recognition signals for allograft rejection. In order to clarify the localization of Ia within islets of Langerhans in animals most commonly used as transplantation models and in humans, we performed both light microscopic (LM) and electron microscopic (EM) immunocytochemical studies with the following panel of monoclonal antibodies directed against Ia: B1F6 (antidog, antirat, and antihuman Ia) and B2E8 (antidog and antihuman Ia), generated in our laboratory; OX6 (antirat Ia); and L243 (antihuman Ia). By LM, B1F6-labeled or B2E8-labeled dog islets and B1F6-labeled or OX6-labeled rat islets all exhibited Ia-specific localization on 0-15 spheroidal or stellate cells per islet. Ultrastructural identification of these cells by indirect immunoperoxidase labeling of unfixed isolated islets revealed Ia-specific cell surface binding mostly on sparsely distributed cells that exhibited ultrastructural characteristics typical of monocytes or macrophages; no specific correlation between cell shape and cell type was apparent by EM. The presence of a resident population of monocytes and macrophages in these islets was confirmed by cytochemical localization of nonspecific esterase activity. Islet endothelium was Ia-negative, as were endocrine cells. Studies of human islets with B1F6, B2E8, and L243 confirmed our preliminary findings that, although there exists a sparse population of Ia-positive leukocytes similar to those present in dog and rat islets, Ia is also expressed extensively and constitutively on the human islet vascular endothelium. This differential localization of Ia in rats and dogs compared with humans could have important implications for the development of successful strategies for the immunomodulation of human islet allografts. We have now shown by immunopurification of 125I-labeled splenocyte plasma membrane antigens, that our MoAbs B1F6 and B2E8 also recognize porcine Ia, and immunocytochemical studies with these MoAbs demonstrated that Ia is also localized on the vascular endothelium in pig islets. Hence, this species may prove to be uniquely suitable as a model in which the immune response functions of Ia-bearing islet endothelium can be explored.

Animals↗
PubMed1986

Natural history of intrahepatic canine islet cell autografts.

We have serially followed the function of intrahepatic canine islet autografts in 15 beagle dogs for up to 24 mo. Of these, only 20% sustained normal levels of fasting blood glucose for greater than 15 mo posttransplant. Failure of autograft function was accompanied by a preferential loss of well-granulated beta cells in the engrafted islets. The chronic stimulation of an initially marginal intrahepatic beta-cell mass ultimately resulted in metabolic deterioration and loss of beta cells below the minimal threshold required to maintain normal fasting blood glucose levels. It is possible that transplantation of a larger mass of islets would result in indefinite graft function in dogs. However, it remains to be demonstrated in larger mammals, including humans, whether an islet cell mass that is initially adequate in a heterotropic site such as the liver can remain functionally competent over a prolonged period.

Animals↗
PubMed1985

Long-term follow-up of canine segmental pancreatic autografts.

The functional and morphologic characteristics of free-draining, pancreatic segmental autografts (FDPS) were studied in 8 beagle dogs that had survived longer than 4 yr. After pancreatectomy, animals received FDPS autografts of the left pancreatic limb, representing approximately one-third of the total pancreas with iliac vessel anastamoses. The grafted recipients were given pancreatic enzyme supplements (Viokase). After transplantation (tx), all 8 animals sustained fasting euglycemia with no evidence of microvascular complications. After 4 yr, IVGTT revealed K-values (%/min) that were not significantly different from age-matched controls (2.9 +/- 0.5 versus 3.7 +/- 0.6, P greater than 0.05). Mean fasting serum insulin levels were significantly greater in the tx animals (49 +/- 5 microU/ml versus 12.2 microU/ml, P less than 0.001), although the incremental response to i.v. glucose (0.5 g/kg) was less than in controls (P less than 0.05). Mean fasting plasma C-peptide levels (0.09 +/- 0.01 pmol/ml versus 0.21 +/- 0.5 pmol/ml) and peak C-peptide responses to i.v. glucose were both significantly less than in controls. Sequential pancreatic biopsies up to 2.5 yr post-tx showed atrophy of the exocrine pancreas with coalescence of islets and mild fibrosis that did not progress with time. Immunoperoxidase stains confirmed the presence of insulin, glucagon, and somatostatin within nests of islet cells. Four years after transplantation of FDPS autografts in pancreatectomized dogs, excellent function is retained. The consequences of peripheral hyperinsulinemia remain to be determined.

Animals↗
PubMed1985

Successful long-term survival of pancreatic islet allografts in spontaneous or pancreatectomy-induced diabetes in dogs. Cyclosporine-induced immune unresponsiveness.

Nineteen pancreatectomized beagles and three spontaneously diabetic dogs were recipients of canine islet allografts from one or more unrelated donors. The islets, enriched 30-45-fold for endocrine cells and contained in a packed cell volume of less than 1.5 ml, were engrafted in the livers of recipient animals. Treatment of diabetic recipients with cyclosporine (CsA) was begun 3-5 days before islet transplantation and the initial dosage was adjusted to attain and maintain CsA serum trough levels between 400 and 600 ng/ml. Five dogs with CsA levels less than this (155 +/- 35 SEM ng/ml) at the time of transplantation promptly rejected their grafts, whereas rejection was encountered in only 1 of 17 diabetic animals in which the initial level exceeded 400 ng/ml. CsA was discontinued 30, 60, or 90 days after continuous therapy in 10 animals. Graft failure was observed 2 mo after stopping CsA in 1 animal and 5 mo in the other. Eight other islet allograft recipients have sustained fasting euglycemia for 7 and 8 mo in 2 and for at least 2 mo in the remainder. These results demonstrate that short-term CsA therapy prolongs survival of islet allografts and induces a state of immune unresponsiveness to islet alloantigens in dogs with experimental and spontaneous diabetes. The findings are unique for a nonrodent mammal and thus hold promise that similar results may be achieved for islet allografts of other mammalian species, including humans.

Animals↗
PubMed1984

A ganglioside antigen on the rat pancreatic B cell surface identified by monoclonal antibody R2D6.

In an attempt to identify B cell specific antigens, we have generated a mouse monoclonal antibody, R2D6, which is directed against plasma membranes of rat pancreatic B cells but against no other pancreatic cells. R2D6 crossreacted with mouse and guinea pig B cells, but not with human or dog. The B cell specificity of R2D6 was utilized in fluorescence-activated cell sorting to prepare highly enriched separate populations of viable pancreatic islet B cells and A cells. R2D6 also recognized adrenal chromaffin cells, secretory cells in the anterior pituitary, and the myenteric plexus of the gastrointestinal tract. Trypsin, chymotrypsin, papain, ficin, and pronase had no effect on R2D6-binding to dissociated rat islet cells. However, neuraminidase treatment of intact cells reduced R2D6-binding by 75%. The antigen recognized by R2D6, Ag(R2D6), could be quantitatively extracted from rat islets by dichloromethane/methanol (2:1) and, after drying, was soluble in methanol alone as well as in phosphate-buffered saline. When the dichloromethane/methanol extract (DME) was bound to polyvinylchloride microtiter plates, antigenic activity was retained and remained insensitive to pronase. In this solvent-extracted form, antigenic activity was totally destroyed by neuraminidase. Therefore, sialic acid is either an integral part of, or is related sterically to the binding site (epitope) for R2D6. In high performance thin-layer chromatographs of the DME, developed in 60:40:9 chloroform/methanol/2.5 N ammonia, Ag(R2D6) migrated with a relative mobility (Rf) of 0.54 +/- 0.07 (n = 3), which was a position nearly coincident with the purified brain ganglioside, GD1a. The antigen bound to DEAE-Sephacel, was not inactivated by mild treatment with base (which hydrolyzes phospholipids) and eluted in ganglioside fractions upon C18 Sep-Pak and upon silicic acid chromatography. Hence, the solubility characteristics, enzyme sensitivities, and behavior of Ag(R2D6) in four chromatography systems are consistent with its identification as a ganglioside.

Animals↗
PubMed1983

Experimental diabetes mellitus and age-simulated changes in intact rat dermal collagen.

Alterations in the physical properties of dermal collagen by streptozotocin-induced diabetes mellitus were investigated in young adult Lewis rats by mounting standardized rings of tail skin on an Instron Universal Testing Apparatus and measuring the thermally induced isometric contraction and stress at rupture of the tissue. Diabetes significantly increased the maximum tension (Tmax) of the contraction and raised the temperature for the Tmax while the stress at rupture (TR) was unaffected when compared with values for controls fed ad libitum and controls fed restricted diets for weight loss equivalence. The diabetes-mediated changes in thermal contractility appeared to be independent of the collagen concentration or negative caloric balance and resembled the reported age-related change in rat skin collagen.

Aging↗
PubMed1982

A method for large-scale, high-yield isolation of canine pancreatic islets of Langerhans.

A modified collagenase digestion method is described for the isolation of large numbers of islets from the canine pancreas (approximately 3,500 islets/g). The islets isolated by this technique remained viable and released insulin in response to secretagogues after one week of maintenance in tissue culture. Islets isolated from a single donor pancreas were re-implanted into the spleen of the same animal made diabetic by subtotal pancreatectomy and two injections fo streptozotocin. Hyperglycemia was corrected in two dogs and decreased in a third dog followed for 30 days. The islet isolation method is described, therefore, provides a sufficiently large yield of viable islets from one donor pancreas to correct or improve diabetes in a recipient animal.

1-Methyl-3-isobutylxanthine↗
PubMed1982

The possible importance of contact between pancreatic islet cells for the control of insulin release.

Insulin secretion was studied using adult rat intact islets, dissociated isolated islet cells, and isolated islet cells that had been allowed to reaggregate. The three preparations were maintained for 2 h in tisue culture medium at 37 C in order to allow for equilibration after the isolation procedures and to permit restoration of contacts between the reaggregated cells. The isolated cells appeared well preserved at the ultrastructural level. Evidence for intimate contacts between the reaggregated cells was demonstrated by the reappearance of gap junctions between adjacent cells. Basal insulin release (2.8 mM glucose) during 30 min was elevated in the isolated cell suspension but was restored to the level found in intact islets when isolated cells from the same population were reaggregated. The elevated basal release did not appear to be due to cell damage since there was a commensurate increase in the rate of insulin biosynthesis relative to intact islets. Although there was a marked stimulation of insulin release from the intact islets at 16.7 mM glucose, the response was smaller in the reaggregated cells and in the isolated cell suspension. All three preparations responded to elevated cAMP levels evoked by glucagon in the presence of 16.7 mM glucose. Similar results were obtained when insulin release was studied in various preparations derived from newborn rat pancreatic endocrine cells. Thus, basal insulin release was elevated in isolated cells, whereas cultures with cell contacts displayed lower basal insulin release. Taken together, the restoration of lower basal insulin release and the parallel appearance of contacts between the reaggregated cells suggest that these two phenomena are interrelated. Thus, cell contacts may be important in regulating basal insulin release. Whether such regulation is a consequence merely of cell association or of direct communication between cells remains to be established.

Aging↗
PubMed1982

Cephalic phycomycosis: a report of eight cases.

Phycomycosis is the preferred terminology to define a fungal disease which may be devastating and fatal. It is caused by a nonseptate hyphae, class phycomycetes and genus (Rhizopus, Mucor, Absidia). Phycomycosis in man is usually associated with debilitating diseases such as: diabetes mellitus, leukemia and immunosuppressive conditions. The cephalic phycomycosis has two forms: 1. rhino-orbital cerebral which may be fatal, and 2. rhino-paranasal sinuses form which usually has a benign clinical course. From 1943 to 1967, only 45 cases of the cephalic form were described with a mortality rate of 50%. Since then several series have been added to the literature with improved survival, probably due to the addition of amphotericin B to the therapy. Even with modern therapy, the mortality rate is still about 30%. Modern technology C.T. scan is very helpful to establish orbital and intracranial extension. When intracranial involvement is present, the prognosis is dismal. Our series of 8 patients is reported.

Adult↗
PubMed1982

Insulin and multiplication stimulating activity (an insulin-like growth factor) stimulate islet (beta-cell replication in neonatal rat pancreatic monolayer cultures.

A possible role for insulin in stimulating islet beta-cell replication was examined in neonatal rat pancreatic monolayer cultures. Addition of insulin to serum-free medium increased the mitotic index and stimulated dose-dependent increases in [3H]-thymidine incorporation in nuclei of islet beta-cells in aldehyde-thionine-stained autoradiographs. The effects of insulin were not associated with any significant changes in glucagon or somatostatin levels in the culture media. Multiplication stimulating activity (MSA), an insulin-like growth factor, was about 100-fold more potent than insulin: 3 ng/ml MSA stimulated a half-maximal increase in thymidine labeling of beta-cell (+63%, P less than 0.005), whereas 300 ng/ml insulin was required for a similar effect. The maximal effects of insulin and MSA were similar, and the combination of maximal stimulatory concentrations of MSA (30 ng/ml) and insulin (3000 ng/ml) was not more effective than either substance added alone, suggesting that both peptides act on the same mechanism(s) regulating beta-cell replication. Furthermore, an antibody to the insulin receptor did not prevent the stimulatory effects of either insulin or MSA on thymidine labeling of beta-cells. These results demonstrate that insulin can stimulate islet beta-cell replication directly, possibly through a receptor for MSA or another insulin-like growth factor.

Animals↗