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Biomedical subjects

T Coffman

Publications and source records attributed to T Coffman.

18 recordsLinked to original sources
PubMed2000

H2-DMalpha(-/-) mice show the importance of major histocompatibility complex-bound peptide in cardiac allograft rejection.

The role played by antigenic peptides bound to major histocompatibility complex (MHC) molecules is evaluated with H2-DMalpha(-/)- mice. These mice have predominantly class II-associated invariant chain peptide (CLIP)-, not antigenic peptide-bound, MHC class II. H2-DMalpha(-/)- donor heart grafts survived three times longer than wild-type grafts and slightly longer than I-A(beta)(b)-(/)- grafts. Proliferative T cell response was absent, and cytolytic response was reduced against the H2-DMalpha(-/)- grafts in vivo. Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection. Removal of both H2-DMalpha and beta2-microglobulin (beta2m) in cardiac grafts lead to greater (8-10 times) graft survival, whereas removal of beta2m alone did not have any effect. These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

Animals↗
PubMed1998

Inhibition of adenosine-1 receptor-mediated preglomerular vasoconstriction in AT1A receptor-deficient mice.

The effect of the adenosine type 1 receptor agonist N6-cyclohexyladenosine (CHA) on glomerular vascular reactivity was studied in male angiotensin II type 1A (AT1A) receptor knockout mice (9). Vascular reactivity was assessed as the response of stop-flow pressure (PSF) to infusion of CHA into loops of Henle using micropuncture techniques. In AT1A +/+ mice at ambient arterial blood pressure (96.7 +/- 2.8 mmHg), the presence of CHA (10 (-5) M) in the perfusate increased PSF responses from 6.8 +/- 0.6 to 14.3 +/- 0.9 mmHg when the loop of Henle of the index nephron was perfused and from 0.7 +/- 0.3 to 12.3 +/- 1.0 mmHg when the loop of an adjacent nephron was perfused. At reduced arterial blood pressure (82.8 +/- 1. 3 mmHg), index nephron perfusion with CHA increased PSF responses from 4.5 +/- 0.3 to 9.4 +/- 0.4 mmHg. In AT1A -/- mice with a mean arterial blood pressure of 80 +/- 1.9 mmHg, CHA increased PSF responses only from 0.1 +/- 0.3 to 3.6 +/- 0.54 mmHg during index nephron perfusion and from 0.25 +/- 0.2 to 2.7 +/- 0.55 mmHg during adjacent nephron perfusion, significantly less than in wild-type animals (P < 0.001). Responses to CHA were intermediate in AT1A +/- mice. Thus AT1A receptor knockout mice show a markedly reduced constrictor response to CHA both in the presence and absence of simultaneous activation of the tubuloglomerular feedback system. These data support the notion of a functional interaction between adenosine and angiotensin II in the regulation of afferent arteriolar tone.

Adenosine↗
PubMed1998

Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice.

Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1A receptors stimulate changes in cytosolic calcium concentration ([Ca2+]i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT1A/AT1B receptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1B receptor mRNA but not that for the AT1A receptor. In wild-type cells with AT1A present, Ang II (10(-7) mol/L) produces a characteristic rapid peak increase in [Ca2+]i of 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca2+]i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca2+]i changes produced by Ang II were similar in cells that lacked AT1A receptors but possessed AT1B receptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT1A receptors suggests that non-AT1A receptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT1A and non-AT1A receptors share common signal transduction pathways. The AT2 receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2 receptors and/or an absence of their linkage to [Ca2+]i pathways. The nonpeptide AT1 receptor blocker losartan antagonizes Ang II-induced [Ca2+]i increases in both cell groups, supporting mediation by native AT1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT1A-deficient VSMCs that is mediated by an endogenous losartan-sensitive AT1B receptor.

Angiotensin II↗
PubMed1997

Absence of tubuloglomerular feedback responses in AT1A receptor-deficient mice.

Experiments were performed in a recently generated strain of mice with an angiotensin II AT1A-receptor null mutation (M. Ito, M. I. Oliverio, P. J. Mannon, C. F. Best, N. Maeda, O. Smithies, and T. M. coffman. Proc. Natl. Acad. Sci. USA 92: 3521-3525, 1995) to examine the effects of chronic AT1A receptor deficiency on tubuloglomerular feeback (TGF) responses. All animals were genotyped by polymerase chain reaction using primers designed to amplify sequences from the deleted AT1A gene and from the neomycin resistance gene. Normal mice (AT1A +/+) and mice heterozygous (AT1A +/-) and homozygous (AT1A -/-) for the gene disruption were anesthetized, and stop-flow pressures (PSF) were determined during changes in loop perfusion rate with previously established micropuncture methods. In five AT1A +/+ mice (26 tubules) mean PSF at zero loop flow was 37.2 +/- 1.5 mmHg, falling to 28.2 +/- 1.9 mmHg at a flow of 45 nl/min (P < 0.0001). Flow rate causing the half-maximum response (V1/2) was 8.7 +/- 0.4 nl/min. In four AT1A +/- animals (19 tubules) mean PSF at zero flow was 39.9 +/- 2.4 mmHg, falling to 34.8 +/- 2.7 mmHg at 45 nl/min (mean V1/2 8.6 +/- 1.04 nl/min). In five AT1A -/- mice (24 tubules) PSF was not significantly affected by loop flow with PSF averaging 33.9 +/- 1.7 mmHg at zero flow and 33.2 +/- 1.6 mmHg at 45 nl/min (not significant). Mean arterial blood pressures in the anesthetized and laparotomized mice were 91.8 +/- 2.2, 97.1 +/- 3, and 80.7 +/- 3.2 mmHg in the AT1A +/+, AT1A +/-, and AT1A -/- animals, respectively. Blood pressure responses to exogenous angiotensin II were greatly blunted in the AT1A -/- mice. We conclude that AT1A receptor-mediated effects of angiotensin II are in essential component of TGF responsiveness under chronic conditions. Our studies show the feasibility of using complex micropuncture methods in mice, an approach that widens the potential of genetically altered mouse strains as experimental models.

Animals↗
PubMed1993

Improved renal function in mouse kidney allografts lacking MHC class I antigens.

The immunological responses that lead to rejection of organ and tissue transplants are triggered by the recognition of proteins encoded within the MHC. The relative contributions of responses directed toward MHC class I compared with class II in the loss of functional integrity of vascularized organ grafts have been difficult to define. The recent development of technologies which allow the generation of mice in which specific genes have been altered by gene targeting offers a new approach to addressing this question. We examine here the rejection of kidney allografts from mice lacking native MHC class I Ag. These mice were obtained from embryonic stem cells in which the beta 2 microglobulin (beta 2m) gene had been disrupted by homologous recombination. We found a significant improvement in function of renal allografts from MHC class I-deficient donors compared with allografts from donors with normal MHC class I expression. Surprisingly, the improved function of the MHC class I-deficient grafts was not associated with differences in mononuclear inflammatory cell infiltration of these grafts nor in differences in alloreactive proliferative or cytotoxic T cell responses. However, we did find differences in alloantibody response between the groups. Recipients of control allografts produced antibodies against both donor MHC class I and II, whereas recipients of MHC class I-deficient grafts formed alloantibodies primarily against donor MHC class II Ag. These studies confirm that immune responses directed toward donor MHC class I alloantigens contribute to kidney transplant dysfunction in this model. Also, these findings suggest that, at least for renal transplants, genetic manipulations which reduce MHC class I expression may be effective in overcoming some of the effects of MHC incompatibility.

Animals↗
PubMed1993

Transgenic tubular cell expression of class II is insufficient to initiate immune renal injury.

Autoimmune disease in mouse models of lupus nephritis is associated with enhanced renal tubular epithelial cell (TEC) expression of major histocompatibility complex (MHC) class II (Ia) molecules. It is unknown whether de novo TEC expression of syngeneic la alone can initiate immune attack or whether expression is secondary to cytokines released by infiltrating lymphocytes. To establish if the expression of high levels of self-MHC molecules alone can initiate immune renal injury in the adult animal, kidneys from transgenic C57BL/6 (B6) mice (Ins-I-E) bearing constitutively high levels of I-Eb on proximal TEC were transplanted into nephrectomized male B6 x C3H F1 hybrid mice (I-Eb/k). Control mice received kidneys from I-Eb negative, nontransgenic B6 mice, and all transplant recipient mice were evaluated for renal disease. At the end of the study (> 8.3 months mean survival), the transgenic transplant recipients did not become proteinuric (< 1+ urinary protein) and had normal serum creatinine levels (control = 95 +/- 8 versus transgenic transplants = 116 +/- 23 mumol/L; N = four/group), and the kidneys remained histologically normal. These results establish that the expression of high levels of transgenic MHC class II molecules on TEC is insufficient to initiate autoimmune injury in this model. It is suggested that, in addition to MHC class II molecules, other signals or accessory molecules are required from TEC to initiate immune renal injury.

Animals↗
PubMed1992

Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients.

The effects of a 48-hour 0.5 mg/kg/hr infusion of the thromboxane synthase inhibitor pirmagrel were studied in 10 renal allograft recipients with cyclosporine nephrotoxicity. Plasma concentrations reached a mean steady-state plasma level of 1798 +/- 481 ng/ml. Biphasic, rapid elimination of pirmagrel was observed with a distribution half-life of 6.7 minutes and a terminal half-life of 73 minutes. Plasma clearance and the volume of distribution of the drug were 300 +/- 87 ml/hr/kg and 497 +/- 232 ml/kg, respectively. The pharmacodynamic effects of pirmagrel were marked by a mean 96% suppression of serum thromboxane B2 (TXB2), which coincided with a suppression of urinary excretion of TXB2, 2,3-dinor-TXB2, and 11-dehydro-TXB2 of 85% +/- 8%, 91% +/- 5%, and 89% +/- 9%, respectively. Urinary excretion of all thromboxane metabolites measured at the end of 1 week after termination of infusion was returned to the baseline. In conclusion, pirmagrel caused effective and sustained suppression of all thromboxane derived metabolites in plasma and urine during continuous infusion in kidney transplant patients receiving cyclosporine.

Adult↗
PubMed1992

Nursing home outbreak of influenza A (H3N2): evaluation of vaccine efficacy and influenza case definitions.

OBJECTIVES: Describe an outbreak of influenza A (H3N2); provide an analysis of vaccine efficacy; measure the sensitivity, specificity, and positive predictive value of 3 clinical case definitions of influenza. SETTING: A nursing home in Washington County, Maryland. The outbreak involved 52 residents (attack rate = 47.7%) and at least 10 of 140 employees (minimum attack rate = 7.1%). RESULTS: Twenty-five residents exhibited a 4-fold or greater increase in titer to influenza A/Sichuan/2/87. Vaccine efficacy was measured at -7.1%, suggesting that the influenza vaccine in 1988/1989 did not offer optimal protection against influenza A infection for the institutionalized elderly. CONCLUSIONS: The outbreak was a clear indicator of the need for rapid diagnosis. With the use of rapid diagnostic tests, influenza A could have been detected in time to use amantadine.

Aged↗
PubMed1992

Thromboxane augmentation of alloreactive T cell function.

Thromboxane (Tx) plays a vital role in the dysfunction and ultimate rejection of MHC-disparate renal allografts. In addition to its potent vasoconstrictory properties, in vivo studies have implied that Tx is capable of promoting immune cytotoxic T cell function within transplants. In this study, we have examined the in vitro effect of Tx inhibition on alloreactive immune cells using MHC-disparate mouse strain combinations. Coculture of either Tx-synthetase or Tx-receptor inhibitors modified the response of unprimed mouse lymphoid populations in a primary MLR, implying that Tx inhibition and not endoperoxide shunting was responsible for the modulatory effects seen. For example, B10.S lymphoid cells displayed decreased proliferation to H-2 disparate B10.A cells with Tx inhibitors present during the MLR, at pharmacologically active drug concentrations. Moreover, in vitro addition of TxA2 had an augmentory effect on the response in the primary and secondary MLR. Interleukin 2 production and percentages of T cell populations in the primary MLR were not affected by the presence of these compounds, although CD4 and CD8 expression was often increased in the treated populations. Finally, alloreactive primed effector cells also displayed reduced proliferation to specific alloantigen in a secondary MLR when Tx inhibitors were also present, although responses to IL-2 by T cells were not influenced by thromboxane inhibition. These data imply that thromboxane is an important immunoregulatory mediator capable of potentiating the function of naive and primed alloreactive immune T cell populations crucial to the rejection of the transplant.

Animals↗
PubMed1990

Thromboxane receptor blockade improves cyclosporine nephrotoxicity in rats.

Cyclosporine A (CyA) nephrotoxicity is associated with impaired renal hemodynamic function and increased production of the vasoconstrictor eicosanoid thromboxane A2 (TxA2). In CyA toxic rats, renal dysfunction can be partially reversed by inhibitors of thromboxane synthase. However, interpretation of these results is complicated since inhibition of thromboxane synthase may cause accumulation of prostaglandin endoperoxides that can act as partial agonists at the TxA2 receptor and may blunt the efficacy of treatment. Furthermore, these endoperoxides may be used as substrate for production of vasodilator prostaglandins causing beneficial effects on hemodynamics which are independent of thromboxane inhibition. To more specifically examine the role of TxA2 in CyA toxicity, we investigated the effects of the thromboxane receptor antagonist GR32191 on renal hemodynamics in a rat model of CyA nephrotoxicity. In this model, administration of CyA resulted in a significant decrease in glomerular filtration rate (GFR) (2.85 +/- 0.26 [CyA] vs 6.82 +/- 0.96 ml/min/kg [vehicle]; p less than 0.0005) and renal blood flow (RBF) (21.65 +/- 2.31 [CyA] vs 31.87 +/- 3.60 ml/min/kg [vehicle]; p less than 0.025). Renal vascular resistance (RVR) was significantly higher in rats given CyA compared to animals treated with CyA vehicle (5.32 +/- 0.55 [CyA] vs. 3.54 +/- 0.24 mm Hg/min/ml/kg [vehicle]; p less than 0.05). These renal hemodynamic alterations were associated with a significant increase in urinary excretion of unmetabolized, "native" thromboxane B2 (TxB2) (103 +/- 18 [CyA] vs 60 +/- 16 pg/hour [vehicle]; p less than 0.05). Only minimal histomorphologic changes were apparent by light microscopic examination of kidneys from both CyA and vehicle treated animals. However, with immunoperoxidase staining, a significantly greater number of cells expressing the rat common leukocyte antigen was found in the renal interstitium of rats given CyA. There was no detectable increase in monocytes/macrophages in the kidneys of CyA toxic animals. In rats treated with CyA, intraarterial infusion of GR32191 at maximally tolerated doses significantly increased GFR and RBF, and decreased RVR. Although both RBF and RVR were restored to levels not different from controls, GFR remained significantly reduced following administration of GR32191. These data suggest that the potent vasoconstrictor TxA2 plays an important role in mediating renal dysfunction in CyA nephrotoxicity. However, other factors may be important in producing nephrotoxicity associated with CyA.

Animals↗
PubMed1985

Plasma free cortisol in depressive illness--a review of findings and clinical implications.

Measurements of a variety of parameters of biologically active cortisol indicate that a small number of patients with depressive illness have significantly elevated levels of unbound plasma cortisol. Abnormalities in corticosteroid binding globulin do not account for the hypercortisolemia, and elevated urinary levels of free cortisol confirm the data obtained for plasma free cortisol. Direct measurements of free cortisol suggest that the absence of physical effects of cortisol in patients with depression is related to the very mild elevation in plasma levels of free cortisol in these patients and that high levels are not sustained throughout the day as they are in patients with pathologic glucocorticoid excess. The apparent discrepancy between elevated total cortisol levels and the mild elevation of unbound plasma cortisol is best explained by the generous binding capacity of corticosteroid binding globulin. Total cortisol levels of greater than 25 micrograms/dl are necessary to saturate the binding sites of corticosteroid binding globulin. Only then can free cortisol be detected in plasma. Although these studies suggest that unbound plasma cortisol is elevated, whether these levels represent biologically active cortisol in other tissue sites as well, particularly the central nervous system, is still unclear. It is well accepted that discrete binding sites for cortisol and dexamethasone occur in hypothalamic and pituitary tissue, but the mechanism of glucocorticoid regulation of these binding sites has not been elucidated. Cortisol levels in cerebrospinal fluid correspond closely to plasma levels of unbound cortisol. Ruf and Steiner have shown that corticosteroid responsive neurons are present in the periventricular gray matter of the third ventricle, where other investigators have identified active ependymal transport mechanisms for cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressive Disorder↗
PubMed1982

Effects of two models of hypercalcemia on renal acid base metabolism.

The effects of two models of chronic hypercalcemia on renal acid-base metabolism were studied in rats. In the first series of experiments, rats were rendered hyperparathyroid by the autologous grafting of 20 to 24 parathyroid glands into a single recipient. Hypercalcemia (5.48 +/- 0.03 mEq/liter in high PTH animals, 4.96 +/- 0.06 mEq/liter in pair-fed controls, P less than 0.001) occurred as did metabolic alkalosis (plasma total carbon dioxide 25.44 +/- 0.47 mEq/liter vs. 23.84 +/- 0.57 in controls, P less than 0.05). The rise in total carbon dioxide was in part a renal tubular effect since urine pH was lower (6.77 +/- 0.04 vs. 6.95 +/- 0.04, day 5, P less than 0.01) bicarbonaturia less (165 +/- 26 vs. 283 +/- 28 mumoles/24 hr, day 5, P less than 0.01) and titratable acid (TA) excretion increased (164 +/- 43.4 vs. 48.2 +/- 2.53 mEq/24 hr, day 5, P less than 0.01) in hyperparathyroid animals vs. pair-fed controls. To test the specific role of hypercalcemia versus PTH in this effect, normoparathyroid animals were treated with 1.25 (OH)2 vitamin D3 or SHAM injected, Urinary cAMP was reduced in these animals (0.030 +/- 0.004 mumoles/8 hr) compared to hyperparathyroid rats (0.055 +/- 0.01 mumoles/8 hr P less than 0.05) suggesting differences i PTH levels. Hypercalcemia occurred in 1,25(OH)2 vitamin D treated animals as did increased plasma total carbon dioxide and urinary TA while urinary bicarbonate excretion and urinary pH were reduced. Because hypercalcemia was associated with elevated total carbon dioxide in both models, it is proposed that chronic hypercalcemia stimulated renal acid excretion and in a sustained manner results in metabolic alkalosis, at least in part, on a renal basis.

Acid-Base Equilibrium↗
PubMedDate not supplied

Intravillous eicosanoid compartmentalization and regulation of placental blood flow.

OBJECTIVE: To determine the roles of the eicosanoids thromboxane and prostacyclin, and their compartmentalization, in the regulation of placental blood flow. METHODS: First, the sites of production of thromboxane and prostacyclin were determined within the placental villus using immunohistochemical staining for thromboxane and prostacyclin synthetase. Second, the production of both eicosanoids was studied in cultured trophoblasts and compared with that in the villous core by measuring the metabolites thromboxane B2 and 6-keto-prostaglandin F 1 alpha. Finally, eicosanoid production was assessed in intact villi after stimulation by an acute change in oxygen content, 5% to 95%. RESULTS: Immunohistochemical staining showed that thromboxane production was primarily within the trophoblasts, whereas prostacyclin production was localized to the endothelial cells within the villi. In culture, we found preferential production of prostacyclin by the villous core cells and increased production of thromboxane by trophoblasts. Perifusion of intact villi demonstrated increased production of thromboxane by trophoblasts in response to an increase in oxygen content. Prostacyclin levels were too low to be detected. CONCLUSIONS: Placental blood flow appears to be regulated by compartmentalized eicosanoids, with thromboxane affecting primarily the maternal side of the placental circulation and prostacyclin affecting primarily the fetal side.

6-Ketoprostaglandin F1 alpha↗