Prevalence of hepatitis B virus infections in nonhuman primates

The aim of this study was to determine the prevalence of hepatitis B virus (HBV) infection in nonhuman primates. Serum samples from Europe, Thailand and Vietnam were analyzed. Sera obtained from 262 apes and 454 monkeys were tested for HBV infection serologically and for HBV DNA using nested PCR (nPCR). A total number of 198 ape sera and all but one (Cercopithecus aethiops) of the 4543 monkey sera had no serological signs of HBV infection. Among the 64 of 262 (24.4%) seropositive ape sera, we found, as in humans, different stages of HBV infection: very early HBV infection, active infection with high level of infectivity, virus carriers with low infectivity, and passed HBV infection. In the cases with passed infection, 47.8% harbored HBV DNA in the presence of protective antibodies to the HBV surface antigen (HBsAb). This indicates HBV persistence in apes despite immune control. In contrast to apes, in monkeys HBV infection is a very rare event.     

Molecular epidemiology of hepatitis B virus variants in nonhuman primates

We characterized hepatitis B virus (HBV) isolates from sera of 21 hepatitis B virus surface antigen-positive apes, members of the families Pongidae and Hylobatidae (19 gibbon spp., 1 chimpanzee, and 1 gorilla). Sera originate from German, French, Thai, and Vietnamese primate-keeping institutions. To estimate the phylogenetic relationships, we sequenced two genomic regions, one located within the pre-S1/pre-S2 region and one including parts of the polymerase and the X protein open reading frames. By comparison with published human and ape HBV isolates, the sequences could be classified into six genomic groups. Four of these represented new genomic groups of gibbon HBV variants. The gorilla HBV isolate was distantly related to the chimpanzee isolate described previously. To confirm these findings, the complete HBV genome from representatives of each genomic group was sequenced. The HBV isolates from gibbons living in different regions of Thailand and Vietnam could be classified into four different phylogenetically distinct genomic groups. The same genomic groups were found in animals from European zoos. Therefore, the HBV infections of these apes might have been introduced into European primate-keeping facilities by direct import of already infected animals from different regions in Thailand. Taken together, our data suggest that HBV infections are indigenous in the different apes. One event involving transmission between human and nonhuman primates in the Old World of a common ancestor of human HBV genotypes A to E and the ape HBV variants might have occurred.     

Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival

The common gammac-chain is an essential signaling component shared by all known T cell growth factor (TCGF) receptors (i.e., IL-2, IL-4, IL-7, IL-9, and IL-15). In the present study, we have studied the effect of gammac-chain blockade on T cell activation and allograft rejection. Treatment of B6AF1 (H-2b/d.k) recipient mice with anti-gammac mAbs induced long-term survival of DBA/2 (H-2d) islet allografts (>150 days, n = 8), whereas control Ab-treated mice rejected the islet allografts within 17 days (n = 6). The state of engraftment induced by the anti-gammac mAbs was remarkably stable, as recipient mice bearing the primary islet allografts accepted a second DBA/2 islet allograft without further immunosuppression and systemic administration of high doses of IL-2Ig fusion protein failed to provoke rejection. Blocking the gammac-chain inhibited T cell proliferation and induced T cell apoptosis by repressing expression of Bcl-2. Our data suggest that one means of inducing T cell apoptosis and stable allograft survival can be achieved via gammac-chain blockade.     

Hemolytic complement in nonhuman primates

Hemolytic serum complement activity was quantitatively compared in baboons, squirrel monkeys, cebus monkeys, and cotton-top marmosets. Squirrel monkeys showed the highest activity, and marmosets had the lowest activity. The complement level in squirrel monkeys and tenfold greater than marmosets and almost four times higher than that of man. Cebus monkeys had levels most similar to that of man while the baboon exhibited activity almost as low as that of the marmoset.     

Barusiban, an effective long-term treatment of oxytocin-induced preterm labor in nonhuman primates

Preterm labor (PTL) affects up to 25% of human pregnancies in developing countries, but there are few therapeutic options. Based on the key role of oxytocin (OXT) in labor and parturition, OXT antagonists are a potentially useful class of drugs for PTL. Barusiban is a new selective, potent, and long-acting OXT receptor antagonist. In this study barusiban was given by continuous i.v. infusion to monkeys during the last 3 wk of pregnancy; the monkeys were also given daily doses of OXT to induce uterine contractions and simulate PTL. Barusiban effectively suppressed OXT-induced PTL-like contractions and prevented early delivery. In contrast, fenoterol (a beta2-adrenoceptor [beta2-AR] agonist used as a comparative control) did not inhibit uterine contractions in this model. Barusiban was particularly effective in maintaining low intrauterine pressure (IUP) near the end of pregnancy, which is when IUP in both OXT controls and fenoterol-treated females increased substantially. Although barusiban delayed the onset of labor, it did not prevent normal delivery. These data demonstrate the safety and efficacy of barusiban in reducing uterine contractility in response to repeated OXT challenge, and suggest that barusiban may be therapeutically effective in long-term treatment of PTL.     

Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways

We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.     

The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities

JAK3 is a cytoplasmic tyrosine kinase with limited tissue expression but is readily found in activated T cells. Patients lacking JAK3 are immune compromised, suggesting that JAK3 represents a therapeutic target for immunosuppression. Herein, we show that a Mannich base, NC1153, blocked IL-2-induced activation of JAK3 and its downstream substrates STAT5a/b more effectively than activation of the closely related prolactin-induced JAK2 or TNF-alpha-driven NF-kappaB. In addition, NC1153 failed to inhibit several other enzymes, including growth factor receptor tyrosine kinases, Src family members, and serine/threonine protein kinases. Although NC1153 inhibited proliferation of normal human T cells challenged with IL-2, IL-4, or IL-7, it did not block T cells void of JAK3. In vivo, a 14-day oral therapy with NC1153 significantly extended survival of MHC/non-MHC mismatched rat kidney allografts, whereas a 90-day therapy induced transplantation tolerance (>200 days). Although NC1153 acted synergistically with cyclosporin A (CsA) to prolong allograft survival, it was not nephrotoxic, myelotoxic, or lipotoxic and did not increase CsA-induced nephrotoxicity. In contrast to CsA, NC1153 was not metabolized by cytochrome P450 3A4. Thus, NC1153 prolongs allograft survival without several toxic effects associated with current immunosuppressive drugs.     

Nephroblastomatosis and nephroblastoma in nonhuman primates

Wilms' tumors, or nephroblastomas, are renal embryonal malignancies with a high incidence in humans. Nephroblastomas are uncommon in nonhuman primates. This report describes three cases of spontaneous proliferative renal tumors in young monkeys: two cases of unilateral kidney nephroblastomas in baboons and a nephroblastomatosis in a cynomolgus macaque. Histologically, both baboon tumors were typical of Wilms' tumors found in humans, with proliferative epithelial cells forming tubules and aborted glomeruli, nephrogenic rests and proliferative fibrovascular tissue. The left kidney of the macaque was markedly enlarged and histologically similar to the baboon tumors, although normal kidney architecture was completely effaced by primitive tubules and occasional glomeruli surrounded by edematous stromal tissue. Cytogenetic analysis did not detect any macaque or baboon equivalents to human Wilms' tumor chromosomal abnormalities. By human pathology classification, the diffuse nature of the macaque tumor is more consistent with nephroblastomatosis than nephroblastoma. This differentiation is the first to be reported in a species other than human. The nephroblastomas described here are the first nephroblastomas to be reported in baboons. Our observations indicate that nonhuman primate nephroblastomatosis and nephroblastomas develop in a similar way to Wilms' tumors in humans, although no genetic marker has been associated with nephroblastomas of nonhuman primates thus far.     

Nutritional deficiency anemias in nonhuman primates

The purpose of this report is to review past studies in which anemias, occurred spontaneously in nonhuman primates due to feeding inadequate diets or were induced by feeding diets deficient in a nutrient. Included is a review of anemias induced by deficiencies of iron, niacin, pyridoxine, pantothenic acid, protein, riboflavin, cyanocobalamin, folic acid, ascorbic acid and alpha-tocopherol. The anemia induced by deficiency of each nutrient is discussed with emphasis on the major clinical signs as well as peripheral blood and bone marrow pathology. Results of supplementation of the diet following induction of deficiency states are discussed also. Whenever applicable, a discussion is included of the use of nonhuman primates as animal models for studies simulating parallel nutritional deficiencies in man.     

In vitro fertilization in nonhuman primates

Ovulation induction, sperm capacitation, and fertilization have been studied for over 50 years in nonhuman primates but it has only been in the past 20 years that extensive studies on sizeable numbers of embryos have been carried out. Of over 200 species of nonhuman primates only a few have been studied and the majority of the findings come from studies of the squirrel monkey, baboon, rhesus, and cynomolgus macaque. Nevertheless, the fertilization process appears to be similar to that identified in other mammals and in man.     

Genital Ureaplasmas in nonhuman primates.

Ureaplasmas were isolated from the genital tracts of four of 22 (18.4%) male chimpanzees and eight of 23 (34.8%) female chimpanzees. Twenty-nine female rhesus monkeys, 38 female baboons, one gibbon, and black ape and one Java monkey were shown to be free of genital Ureaplasmas. The rate of reproductive failure among the chimpanzees was high and it is suggested that Ureaplasma may be responsible in part. The chimpanzee may serve as a useful model for human Ureaplasma genital infections.