Impact of human leukocyte antigen molecules E, F, and G on the outcome of transplantation.

BACKGROUND: HLA class I molecules are divided into classic (Ia) and nonclassic (Ib). Nonclassic HLA molecules (E, F, and G) have acquired relevance owing to their immunomodulatory properties and possible repercussions for induction of tolerance in organ transplantation. The objective of this study was to identify the impact of these molecules on transplant success or failure. METHODS: A systematic review of literature was performed with the use of MeSH terms in Pubmed. Clinical trials, randomized clinical trials, case-control studies, and reviews from the past 15 years were included. RESULTS: HLA-E*0103/E*0103 genotype is associated with lower risk of graft-versus-host disease, decreased mortality, and greater disease-free survival after bone marrow transplantation. There were no significant associations between HLA-F and clinical outcomes in any of the studies. Elevated serum levels of HLA-G were associated with a lower incidence of rejection in hepatic and renal transplantation during the 1st year and lower T-cell response after bone marrow, liver, and kidney transplantation. Detection of mRNA of HLA-G1 was also associated with less graft rejection. CONCLUSIONS: Current literature suggests that nonclassic HLA Ib molecules play an important role in immunotolerance in organ transplantation; however, more studies are required to predict outcomes related to specific genotypes.

Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation.

Progress in transplantation has relied on similar human leukocyte antigen (HLA) matching between the donor and the patient, while the role of other immunologic factors like non-HLA markers including minor histocompatibility antigens (miHA) are currently in the forefront. miHA are polymorphic proteins that vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA (MHC class I chain-related gene A). miHA have been well studied in transplantation of hematopoietic precursors, but not in solid organ transplantation. The most important studies in this field relate to incompatibility of H-Y antigen as a risk factor in kidney transplantation, although the findings are still inconclusive. This review presents the role of minor histocompatibility antigens in solid organ transplantation, especially of the kidney.

Regulation of Ca2+-sensitive adenylyl cyclase in gonadotropin-releasing hormone neurons.

In immortalized GnRH neurons, cAMP production is elevated by increased extracellular Ca2+ and the Ca2+ channel agonist, BK-8644, and is diminished by low extracellular Ca2+ and treatment with nifedipine, consistent with the expression of adenylyl cyclase type I (AC I). Potassium-induced depolarization of GT1-7 neurons causes a dose-dependent monotonic increase in [Ca2+]i and elicits a bell-shaped cAMP response. The inhibitory phase of the cAMP response is prevented by pertussis toxin (PTX), consistent with the activation of G(i)-related proteins during depolarization. Agonist activation of the endogenous GnRH receptor in GT1-7 neurons also elicits a bell-shaped change in cAMP production. The inhibitory action of high GnRH concentrations is prevented by PTX, indicating coupling of the GnRH receptors to G(i)-related proteins. The stimulation of cAMP production by activation of endogenous LH receptors is enhanced by low (nanomolar) concentrations of GnRH but is abolished by micromolar concentrations of GnRH, again in a PTX-sensitive manner. These findings indicate that GnRH neuronal cAMP production is maintained by Ca2+ entry through voltage-sensitive calcium channels, leading to activation of Ca2+-stimulated AC I. Furthermore, the Ca2+ influx-dependent activation of AC I acts in conjunction with AC-regulatory G proteins to determine basal and agonist-stimulated levels of cAMP production.

Creating long-term benefits in cleft lip and palate volunteer missions.

The authors present their experience with 15 years of organizing cleft lip and palate surgical volunteer missions in Latin America. The history, basic principles, and objectives of Operation San Jose, a volunteer goodwill program from Christus St. Joseph Hospital in Houston, Texas, are covered. This report addresses the different problems encountered and solutions found. Following the principles set by Operation San Jose, CIRPLAST is a Peruvian foundation for plastic surgery that travels to remote areas in Peru, operating on patients with cleft lip and palate deformities. This report highlights the importance of working with local plastic surgeons and their residents, and emphasizes that the program should be organized by and the operations performed by accredited plastic surgeons and with the auspices and support of the national plastic surgery society and the local medical board. Operation San Jose promotes the creation of long-term benefits by offering a program to teach local surgeons cleft lip and palate repair techniques and to set up guidelines to organize local surgeons so that they can continue this effort by treating their own patients in their own countries.

Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons.

Episodic hormone secretion is a characteristic feature of the hypothalamo-pituitary-gonadal system, in which the profile of gonadotropin release from pituitary gonadotrophs reflects the pulsatile secretory activity of GnRH-producing neurons in the hypothalamus. Pulsatile release of GnRH is also evident in vitro during perifusion of immortalized GnRH neurons (GT1-7 cells) and cultured fetal hypothalamic cells, which continue to produce bioactive GnRH for up to 2 months. Such cultures, as well as hypothalamic tissue from adult rats, express GnRH receptors as evidenced by the presence of high-affinity GnRH binding sites and GnRH receptor transcripts. Furthermore, individual GnRH neurons coexpress GnRH and GnRH receptors as revealed by double immunostaining of hypothalamic cultures. In static cultures of hypothalamic neurons and GT1-7 cells, treatment with the GnRH receptor antagonist, [D-pGlu1, D-Phe2, D-Trp(3,6)]GnRH caused a prominent increase in GnRH release. In perifused hypothalamic cells and GT1-7 cells, treatment with the GnRH receptor agonist, des-Gly10-[D-Ala6]GnRH N-ethylamide, reduced the frequency and increased the amplitude of pulsatile GnRH release, as previously observed in GT1-7 cells. In contrast, exposure to the GnRH antagonist analogs abolished pulsatile secretion and caused a sustained and progressive increase in GnRH release. These findings have demonstrated that GnRH receptors are expressed in hypothalamic GnRH neurons, and that receptor activation is required for pulsatile GnRH release in vitro. The effects of GnRH agonist and antagonist analogs on neuropeptide release are consistent with the operation of an ultrashort-loop autocrine feedback mechanism that exerts both positive and negative actions that are necessary for the integrated control of GnRH secretion from the hypothalamus.

Muscarinic regulation of intracellular signaling and neurosecretion in gonadotropin-releasing hormone neurons.

Agonist activation of cholinergic receptors expressed in perifused hypothalamic and immortalized GnRH-producing (GT1-7) cells induced prominent peaks in GnRH release, each followed by a rapid decrease, a transient plateau, and a decline to below basal levels. The complex profile of GnRH release suggested that acetylcholine (ACh) acts through different cholinergic receptor subtypes to exert stimulatory and inhibitory effects on GnRH release. Whereas activation of nicotinic receptors caused a transient increase in GnRH release, activation of muscarinic receptors inhibited basal GnRH release. Nanomolar concentrations of ACh caused dose-dependent inhibition of cAMP production that was prevented by pertussis toxin (PTX), consistent with the activation of a plasma-membrane Gi protein. Micromolar concentrations of ACh also caused an increase in phosphoinositide hydrolysis that was inhibited by the M1 receptor antagonist, pirenzepine. In ACh-treated cells, immunoblot analysis revealed that membrane-associated G(alpha q/11) immunoreactivity was decreased after 5 min but was restored at later times. In contrast, immunoreactive G(alpha i3) was decreased for up to 120 min after ACh treatment. The agonist-induced changes in G protein alpha-subunits liberated during activation of muscarinic receptors were correlated with regulation of their respective transduction pathways. These results indicate that ACh modulates GnRH release from hypothalamic neurons through both M1 and M2 muscarinic receptors. These receptor subtypes are coupled to Gq and Gi proteins that respectively influence the activities of PLC and adenylyl cyclase/ion channels, with consequent effects on neurosecretion.

NMDA receptor antagonists block stress-induced prolactin release in female rats at estrus.

In order to evaluate the role of glutamate in prolactin secretion, we examined the effects of N-methyl-D,L-aspartic acid (NMDA) receptor antagonists on serum prolactin levels at both resting and restraint-stress conditions in female rats at estrus. NMDA increased basal serum prolactin levels. Administration of the selective NMDA receptor antagonist, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) (5 and 10 mg/kg i.p.), to rats under resting conditions enhanced basal prolactin levels. A low dose of CGS 19755 (3 mg/kg) was unable to modify the hormone serum level. Under stress conditions the pretreatment with CGS 19755 (3 and 5 mg/kg) prevented the increase in serum prolactin levels. This effect was reversed by NMDA (60 mg/kg s.c.). The NMDA receptor antagonist (5 mg/kg) decreased the median eminence concentration of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), without modifying dopamine content. To examine the probable link between serotonin (5-HT) and glutamate in prolactin release, the 5-HT2A/5-HT2C receptor antagonist, ritanserin, was used. Under resting conditions, a dose of 5 mg/kg s.c. blocked the NMDA-induced prolactin release. In rats submitted to restraint, ritanserin decreased the prolactin response and NMDA was unable to correct the stress serum prolactin levels. The 5-HT1A receptor agonist, 8-hidroxypropyl-amino tetralin (8-OH-DPAT) (3 mg/kg s.c.), increased basal serum prolactin levels and restored serum prolactin in stressed animals pretreated with CGS 19755 (5 mg/kg). The present data strongly suggest that the glutamatergic system participates in the regulation of prolactin secretion. A stimulation tone seems to be exerted via the tuberoinfundibular dopaminergic system, and the prolactin release evoked by restraint apparently involves glutamate/NMDA receptors linked to a serotoninergic pathway.

Progesterone in vitro increases NMDA-evoked [3H] dopamine release from striatal slices in proestrus rats.

The dopaminergic nerve terminals in rat striatum appear to be an important target for progesterone (Pg) and the excitatory amino acid glutamate. In the present study the possible interaction between glutamate and Pg upon [3H]DA release in striatal slices from rats in proestrus was examined. [3H]DA release was augmented by NMDA in a concentration-dependent manner. The presence of Pg (400 nM) in the perfusion medium produced an amplification of the responses to NMDA (50 microM) as shown by significant increase in the tritium outflow. The NMDA selective antagonists AP-7 (100 microM) and MK-801 (0.1 microM) prevented the effects of both NMDA and NMDA plus Pg on [3H]DA release. In contrast, the AMPA/kainate receptor antagonist CNQX (10 and 20 microM) was ineffective. Furthermore, AP-7 (100 microM) attenuated the enhancing effect of 400 nM Pg on [3H]DA release evoked by 28 mM K+. The antagonist was unable to alter the effect produced by K+ alone. These results indicate a specific action of Pg on dopaminergic terminals mediated by NMDA receptors and suggest a close interaction between glutamate and dopamine systems in the striatum, apparently modulated by progesterone.

Interaction between glutamate and GABA on 3H-noradrenaline release from rat hypothalamus.

Glutamate has been shown to stimulate noradrenaline (NA) release from hypothalamic nerve terminals. In the present study, we evaluated the possible interaction between the excitatory amino acid glutamate and gamma-aminobutyric acid (GABA), an inhibitory transmitter, on noradrenaline (NA) release from mediobasal hypothalamus (MBH) of adult male rats. Hypothalamic slices loaded in vitro with 3H-NA were superfused and exposed to glutamate, N-methyl-D-aspartic acid (NMDA), or kainate (KA). We found that 3H-NA release evoked by the excitatory amino acids glutamate and NMDA was dramatically decreased by GABA. The facilitatory effects of NMDA and KA were prevented concentration-dependently by the GABAB receptor antagonist 2-hydroxy saclofen which restored the NMDA effect. In addition, baclofen blocked K(+)-induced 3H-NA release. Activation of GABAA receptors by muscimol and THIP was ineffective. In conclusion, glutamate and GABA, through GABAB receptors, may interact to modulate NA release from the rat mediobasal hypothalamus.

Regulation of luteinizing hormone-releasing hormone and luteinizing hormone secretion by hypothalamic amino acids.

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

Regulation of luteinizing hormone-releasing hormone and luteinizing hormone secretion by hypothalamic amino acids

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

Release of 3H-noradrenaline by excitatory amino acids from rat mediobasal hypothalamus and the influence of aging.

The present study was designed to analyze the effects of glutamate (GLU) and its agonists on the release of noradrenaline (NA) from the mediobasal region of rat hypothalamus (MBH). Slices from hypothalamus were loaded in vitro with 3H-NA and thereafter exposed to GLU and the glutamate agonists N-methyl-D-aspartic acid (NMDA) and kainate (KA), in superfusion chambers. GLU evoked a significant 3H-NA release in a concentration-dependent manner. The EC50 was 35 mM. 6-Cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a non-NMDA selective antagonist, and amino-7-phosphonoheptanoic acid (AP 7), a NMDA selective antagonist, both decreased the GLU-evoked response to about 50% of its value. NMDA, superfused in Mg(2+)-free Krebs-Ringer, exhibited a greater potency than GLU with an EC50 = 124 microM. KA was also able to evoke 3H-NA release, although overall responses to KA were lower than those of NMDA. The maximal response to KA was a 36% increase of release at a concentration of 200 microM. The effect of KA was blunted by CNQX. NMDA-induced 3H-NA release was progressively altered with age. In old rats (16-18 months) and middle-aged rats (10 months), responses to 200 microM NMDA were decreased respect to young (4 months) male rats. These results show that NMDA and KA receptors mediate the excitatory effects of GLU on NA release from nerve terminals in the MBH and suggest that GLU, in association with NA, participates in the complex mechanisms that regulate neuroendocrine functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of H3-histamine receptors increases the release of prolactin in male rats.

Histamine (HA) stimulates prolactin secretion via H1 and H2 receptors. In the present study, we examined the role of a third subtype of receptor recently described in brain, the H3-HA receptor, on prolactin secretion in male rats. R(-)alpha-methyl-HA (alpha-MHA), a selective H3 receptor agonist, was injected into the lateral ventricle of the brain in freely moving rats. alpha-MHA produced a dose-dependent (1-5 micrograms) and long-lasting increase in plasma prolactin levels. This increase was observed from 15 to 60 min after injection of alpha-MHA. Its stimulatory action was prevented by thioperamide (20 micrograms i.v.t), a selective H3 antagonist. This compound, injected intraventricularly, lacked effect by itself on basal plasma prolactin levels. Neither pyrilamine (H1 antagonist; 60 micrograms i.v.t.) nor ranitidine (H2 antagonist; 60 micrograms i.v.t.) affected alpha-MHA-induced prolactin release. The stimulatory effect was still present when brain HA was depleted by alpha-fluoromethylhistidine (30 mg/kg i.p.). Our findings suggest that alpha-MHA evokes prolactin release by activation of postsynaptic H3 receptors.

Serum biochemical changes in dogs with experimental Leptospira interrogans serovar icterohaemorrhagiae infection.

Inoculation of 2 groups of dogs with 1 X 10(9) and 4 X 10(9) Leptospira interrogans serovar icterohaemorrhagiae produced disease varying from transient fever to uremia and death. Clinical signs of disease in the severely affected dogs were fever, dehydration, depression, and icterus. Laboratory changes in serum of infected dogs included increased urea nitrogen, creatinine, phosphorus, alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase. Chloride concentration decreased in the serum of dogs with severe disease. The icterus in the infected dogs did not appear to be related to hemolytic anemia.