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PubMed2000

Human urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate.

The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynamic homeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD2s < or = 9) approximately an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the most, if not the most, potent mammalian vasoconstrictor identified to date. However, in vitro responses exhibited significant anatomical and/or species-dependency, that is, human U-II was a selective 'aorto-coronary' vasoconstrictor in rats and dogs, inactive in mice and contracted all primate arteries studied. In vivo, this peptide evoked a complex, dose-dependent hemodynamic response in the anesthetized primate, culminating in severe myocardial depression and fatal circulatory collapse. As such, U-II may represent a novel neurohumoral regulator of mammalian cardiovascular physiology and pathology in particular disorders characterized by aberrant vascular smooth muscle and/or myocardial function.

Animals↗
PubMed2004

Evaluation of photopoint photosensitizer mv6401, indium chloride methyl pyropheophorbide, as a photodynamic therapy agent in primate choriocapillaris and laser-induced choroidal neovascularization.

PURPOSE: To assess the potential of a new photosensitizer, indium chloride methyl pyropheophorbide (PhotoPoint MV6401), for ocular photodynamic therapy (PDT) in normal choriocapillaris vessels and experimentally induced choroidal neovascularization in New-World monkeys (Saimiri sciureus). METHODS: PhotoPoint MV6401 (Miravant Pharmaceuticals, Inc., Santa Barbara, CA) was activated at 664 nm using a DD3-0665 (Miravant Systems, Inc., Santa Barbara, CA) 0.5 W diode laser. The efficacy of MV6401 was evaluated by indirect ophthalmoscopy, fundus photography, fluorescein angiography, and histology. The drug and light doses were 0.10 micromoles/kg to 0.3 micromoles/kg and 10 J/cm to 40 J/cm, respectively, and post-injection activation times ranged from +10 minutes to +120 minutes. RESULTS: Best closure of normal choriocapillaris was achieved at a dosage level of 0.15 micromoles/kg in primates. Histology demonstrated that increased post-injection activation times (+60 minutes to +90 minutes) and low laser light doses (10 J/cm to 20 J/cm) in the primate model resulted in selective closure of the choriocapillaris and medium sized choroidal vessels with minimal effect to the retina. Histology from neovascular lesions PDT-treated with MV6401 revealed significant diminution of vascularity, correlating with diminution of leakage observed on angiography. CONCLUSION: PhotoPoint MV6401, indium chloride methyl pyropheophorbide, is a potent photosensitizer that demonstrates both efficacy and selectivity in primate choriocapillaris and laser-induced choroidal neovascularization occlusion. Maximum selectivity was achieved using a post infusion interval of +60 to +90 minutes.

Animals↗
PubMed1987

Prolongation of primate cardiac xenograft survival with cyclosporine.

Cardiac xenotransplantation in nonprimates using traditional immunosuppression (azathioprine and prednisone) or cyclosporine has been unsuccessful or has required doses of immunosuppressants not tolerated by man. This study sought to determine if primate hearts could be transplanted successfully across genus boundaries using a dose of cyclosporine applicable to human transplantation. The hearts of outbred cynomolgus monkeys (Macaca fascicularis) were heterotopically transplanted into the necks of outbred baboons (Papio anubis). Hyperacute rejection did not occur and there were no cyclosporine-induced malignancies or nephrotoxicity. A 12-fold prolongation of mean cardiac xenograft survival to 77 days was accomplished using parenteral cyclosporine and steroids. The histology of rejection was notable for the appearance of reversible rejection on the 30-day biopsies. The histopathologic and immunologic data support the role of both cell-mediated and humoral mechanisms in primate cardiac xenograft rejection. Neither mixed lymphocyte cultures or cytotoxic antibody assays were predictive of graft loss, but there was a significant increase in their respective levels at the time of cessation of graft function. Thus, significant prolongation of primate cardiac graft survival across a genus boundary was accomplished using a dose of cyclosporine similar to that used in human transplantation.

Animals↗
PubMed1999

Prolongation of primate cardiac allograft survival by treatment with ANTI-CD40 ligand (CD154) antibody.

BACKGROUND: We evaluated whether a humanized anti-CD154 antibody (hu5c8) prolongs primate cardiac allograft survival. METHODS: Heterotopic cardiac allografts were performed between MHC class II-mismatched cynomolgus monkeys. Survival was compared between groups treated with a perioperative dosing of hu5c8 (group 1; n=6), sustained dosing with hu5c8 (group 2; n=3), and control regimens (n=4). All recipients received fresh donor-specific transfusions during surgery. RESULTS: Median graft survival was 49 days (range 14 to 56) in group 1 and 106 days (range 56 to 245) in group 2, compared with 5 days (range 5 to 6) for controls (P<0.05 for all comparisons). Lymphocytic infiltrates were often present in hu5c8-treated grafts with stable contractility. Donor-specific mixed lymphocyte reaction was generally preserved. Vasculitis and cellular intimal proliferation were prevalent in rejected grafts but occurred later and were less prevalent in group 2. CONCLUSIONS: Anti-CD154 antibody markedly prolongs the survival of cardiac allografts in primates and is well tolerated. Sustained dosing with hu5c8 yielded improved survival and may be associated with a lower incidence of vascular pathology. We conclude that hu5c8 therapy is an effective approach for inhibiting acute cardiac allograft rejection in primates.

Animals↗
PubMed2000

Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates.

BACKGROUND: Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS). METHODS: Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105. RESULTS: Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05). CONCLUSIONS: Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Actins↗
PubMed2000

Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days.

BACKGROUND: It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates. METHODS: Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs. FINDINGS: The three control animals transplanted with livers from unmodified pigs survived for less than 12 hr. Baboons transplanted with livers from h-DAF transgenic pigs survived for 4 and 8 days. Hyperacute rejection was not detected in the baboons transplanted with hDAF transgenic pig livers; however, it was demonstrated in the three transplants from unmodified pigs. Baboons transplanted with livers from h-DAF transgenic pigs were extubated at postoperative day 1 and were awake and able to eat and drink. In the recipients of hDAF transgenic pig livers the clotting parameters reached nearly normal levels at day 2 after transplantation and remained normal up to the end of the experiments. In these hDAF liver recipients, porcine fibrinogen was first detected in the baboon plasma 2 hr postreperfusion, and was present up to the end of the experiments. One animal was euthanized at day 8 after development of sepsis and coagulopathy, the other animal arrested at day 4, after an episode of vomiting and aspiration. The postmortem examination of the hDAF transgenic liver xenografts did not demonstrate rejection. INTERPRETATION: The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.

Acute Disease↗
PubMed2001

Transplantation of hepatocytes in nonhuman primates: a preclinical model for the treatment of hepatic metabolic diseases.

BACKGROUND: The transplantation of isolated hepatocytes in large animals, including nonhuman primates, must be evaluated before clinical trials are performed. However, in the absence of large transgenic animals and large-animal (as opposed to small-animal) models of genetic deficiencies, it is difficult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this work, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term. METHODS: A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca fascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vitro with a recombinant retrovirus expressing the beta-galactosidase gene and returned to the liver by infusion through a portal catheter left in place. Liver biopsies were performed 4 and 7 d after transplantation. RESULTS: Twenty-four monkeys underwent surgery to define the necessary technical adjustments and to optimize conditions. Six monkeys died. The whole protocol, including the transplantation of genetically marked hepatocytes and procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta-galactosidase gene were widely distributed in the portal tracts, sinusoids, and hepatocyte plates of the host liver 4 and 7 d after transplantation. CONCLUSIONS: We have developed an experimental nonhuman primate model for the evaluation of hepatocyte transplantation. We demonstrated the engraftment and functioning of transplanted hepatocytes in the host liver 4 and 7 d after transplantation.

Animals↗
PubMed2002

Analysis of the control of the anti-gal immune response in a non-human primate by galactose alpha1-3 galactose trisaccharide-polyethylene glycol conjugate.

BACKGROUND: The current limitation to the clinical application of xenotransplantation using pig organs is a rejection process that has been termed delayed xenograft rejection or acute vascular rejection. It is thought that acute vascular rejection may be mediated at least in part by both the continued synthesis, of preexisting, and the induction, posttransplantation, of antibodies against the carbohydrate moiety galalpha1-3gal that is present on glycoproteins and glycolipids of the pig endothelium. The synthesis of these antibodies has proven difficult to control with currently available immunosuppressive agents. METHODS: We have synthesized galalpha1-3gal conjugated polyethylene glycol polymers that can bind to anti-galalpha1-3gal antibodies and tested their activity in non-human primates. RESULTS: These conjugates when administered to non-human primates can substantially reduce the levels of preexisting and control the induction of anti-galalpha1-3gal antibodies. The level of circulating antibody-secreting cells that make anti-galalpha1-3gal antibodies is also reduced. CONCLUSION: These alpha-gal polyethylene glycol conjugates may have the potential to control the anti-gal antibody response in a pig to primate organ transplant setting and may be a useful therapeutic agent in prolonging graft survival.

Animals↗
PubMed2002

Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation.

BACKGROUND: Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy. METHODS: A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually. RESULTS: Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311-911 days), significantly greater than untreated controls (mean survival=7.0 days, P=0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P=0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154. CONCLUSION: These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.

Animals↗
PubMed2000

Inverse correlation of telomerase activity/proliferation of CD4+ T lymphocytes and disease progression in simian immunodeficiency virus-infected nonhuman primates.

Both increased lymphocyte renewal with subsequent exhaustion of the immune system and impaired T-cell renewal have been put forth to account for CD4+ T-cell depletion and development of AIDS in HIV-1-infected humans and SIV-infected nonhuman primates. In the present study, telomeric terminal restriction fragment length and telomerase activity were used as measures of proliferative activity of T lymphocytes from three nonhuman primate species before and after being infected with SIV. In peripheral blood T cells, our data show both species and T-cell-subset-specific differences in proliferative activity accompanied by different patterns of disease progression. A significant postinfection increase in telomerase/proliferative activity in CD4+ T cells from seropositive sooty mangabeys and from normal progressor rhesus macaques was associated with asymptomatic infection or delayed disease progression, respectively, whereas a decrease in telomerase/proliferative activity detected in CD4+ T cells postinfection from SIVsmmPBj14-infected pigtailed macaques was associated with rapid CD4+ T-cell depletion and disease progression. The levels of telomerase activity observed in CD4+ T cells from peripheral blood closely parallelled those seen in CD4+ T cells in lymph node samples from selected animals. Our data suggest that an increase in proliferative activity of T lymphocytes in vivo may be associated with a favorable course of SIV infection in nonhuman primates.

Animals↗
PubMed2004

Evidence of osteoinduction by Grafton demineralized bone matrix in nonhuman primate spinal fusion.

STUDY DESIGN: A nonhuman primate posterolateral lumbar intertransverse process arthrodesis model was used to evaluate osteoinductive bone graft materials. OBJECTIVES: To test two new formulations of Grafton demineralized bone matrix (Flex and Matrix) for evidence of osteoinduction and their potential efficacy as an extender or enhancer for autogenous bone in a previously validated nonhuman primate posterolateral lumbar fusion model. SUMMARY OF BACKGROUND DATA: Whereas several demineralized bone matrix formulations have been shown to be variably osteoinductive in rodent ectopic bone assays and rabbit spine applications, few have demonstrated efficacy in higher species and in more challenging applications such as posterolateral spine fusion. The authors are not aware of any published studies describing any demineralized bone matrix that has been tested in a nonhuman primate posterolateral spine fusion model. METHODS: After approval by the institutional animal care and use committee, eight skeletally mature rhesus macaques underwent single-level posterolateral arthrodesis. In four animals, autograft (4 g/side) was implanted with a piece of human Grafton Flex demineralized bone matrix. In the other four animals, rhesus Grafton Matrix demineralized bone matrix, a new and more porous formulation of Flex, was implanted with autograft (4 g) on one side of the spine, and Matrix with half the amount of autograft (2 g) was implanted on the opposite side. Radiographs were taken at intervals until the animals were killed at 24 weeks. Spinal fusion was evaluated by manual palpation (status was fused or not fused), and computed tomography was done to visualize the amount of bone formation. RESULTS: Fusion was ascertained by palpation in two of four monkeys receiving Flex with autograft and in three of four monkeys receiving Matrix with autograft. Evidence of osteoinduction was seen in all four monkeys on the Matrix with 4 g autograft side, which had larger fusion masses than in the other treatments. Histologic examination showed that the bone formed was normal. CONCLUSIONS: The rhesus Matrix formulation performed better than the human Flex. Evidence of osteoinduction was seen in all four monkeys that received Matrix, which improved the fusion success of autograft. This alone suggested that it might play a role as a graft enhancer, not merely as a graft extender. Human studies are warranted.

Animals↗
PubMed2005

Lower dose of rhBMP-2 achieves spine fusion when combined with an osteoconductive bulking agent in non-human primates.

STUDY DESIGN: A non-human primate lumbar intertransverse process arthrodesis model was used to evaluate the effectiveness of different formulations of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce consistent bone formation. OBJECTIVE: To determine if the combination of rhBMP-2/absorbable collagen sponge (ACS) wrapped around a bulking agent, consisting of a biphasic calcium phosphate/collagen composite, could achieve posterolateral spine fusion with a dose of rhBMP-2 (3.0 mg/side) that previously failed to induce posterolateral fusion in rhesus monkeys with other carriers. SUMMARY OF BACKGROUND DATA: Successful bone induction in both human and non-human primates has required higher concentrations of BMP than were required in lower order models. The Food and Drug Administration approved concentration of rhBMP-2 for interbody fusion (1.5 mg/mL) when delivered on the ACS alone without a bulking agent (doses 3-9 mg/side) has failed to induce clinically relevant amounts of bone formation in a posterolateral spine fusion model in rhesus monkeys. Previously, a higher concentration of 2.0 mg/mL of rhBMP-2 delivered on stacked sheets of a biphasic calcium phosphate ceramic/collagen compression resistant matrix (CRM) was required to achieve fusion in the rhesus monkey and was the basis for this study (doses of 6-12 mg/side). METHODS: Nine skeletally mature, rhesus macaque monkeys underwent single level posterolateral arthrodesis at L4-L5. Two different rhBMP-2 doses were evaluated in 3 delivery configurations. The first 3 monkeys received 10 mg/side (2.5 mL at 4.0 mg/mL) of rhBMP-2 loadeddirectly onto a CRM carrier (15% hydroxyapatite/85%beta-tricalcium phosphate ceramic/collagen matrix), resulting in a final concentration of 2.0 mg/mL. The second 3 monkeys received 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 loaded directly on the CRM carrier, resulting in a 0.6 mg/mL final concentration. Three additional monkeys also received the 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 delivered on an ACS, which was then wrapped around the dry CRM matrix used as a bulking agent, yielding a 1.5 mg/mL final concentration of rhBMP-2 on the sponge wrapped around the bulking agent. The monkeys were euthanized at 24 weeks after surgery. Manual palpation, plain radiographs, computerized tomography, and nondecalcified histology were used to evaluate fusion in a blinded fashion. RESULTS: The 3 monkeys with 10 mg rhBMP-2 placed directly on the CRM carrier (2.0 mg/mL final concentration) achieved solid fusion. The 3 monkeys that underwent fusion with 3 mg of rhBMP-2 placed directly on the CRM carrier (0.6 mg/mL final concentration) failed to achieve fusion. In contrast, the 3 monkeys that underwent fusion with the same 3 mg dose of rhBMP-2 dispensed only on an ACS that was wrapped around the CRM achieved solid bilateral fusion. CONCLUSIONS: This study shows the importance of carrier optimization and final implant protein concentration for the successful delivery of rhBMP-2. By combining the properties of the ACS with the CRM, the required dosage of rhBMP-2 was diminished by more than 3-fold in the non-human primate model. This finding suggests that the currently available concentration of rhBMP-2 (1.5 mg/mL) could be successful for achieving posterolateral spine fusion when combined with an osteoconductive bulking agent that can support the induced new bone formation.

Animals↗
PubMed2005

Mucosal biofilm formation on middle-ear mucosa in a nonhuman primate model of chronic suppurative otitis media.

BACKGROUND: An increased awareness of bacterial biofilms and their formation has led to a better understanding of bacterial infections that occur in the middle ear. Perhaps the best studied pathogen for its propensity toward biofilm formation is Pseudomonas aeruginosa, also the primary pathogen in chronic suppurative otitis media (CSOM). OBJECTIVE: The aim of this study was to determine whether P. aeruginosa forms a biofilm in the middle ear in the setting of CSOM in a nonhuman primate model. METHODS: Cynomolgus monkeys underwent perforation of the tympanic membrane and inoculation of the middle ear with a known biofilm-forming strain of P. aeruginosa. The contralateral ear was used as an internal control and was neither perforated nor infected. At the end of the study period, both ears were irrigated to remove planktonic bacteria, and the middle ear mucosa was removed and examined ultrastructurally using scanning electron microscopy (SEM) for determination of the presence or absence of biofilm formation. MAIN OUTCOME MEASURE: The identification of middle ear biofilm containing rod-shaped bacteria. RESULTS: SEM revealed that P. aeruginosa formed bacterial biofilm in vivo on the middle ear mucosal surface, seen only in the infected ear. Interestingly, biofilm formation caused by cocci was also seen in both the experimental as well as the control ear. CONCLUSION: P. aeruginosa forms biofilms in the middle ear in CSOM in primates. To our knowledge, this is the first report of disease-associated bacterial biofilm in a nonhuman primate model of CSOM. Such a model lays a foundation for much needed study into the role of biofilms in the pathophysiology of CSOM. Should CSOM be caused by biofilms, which is uncertain at this time, development of novel strategies for treatment and prevention may be possible. The finding of both rods and cocci forming biofilms also warrants further investigation.

Animals↗
PubMed2003

Porcine cytomegalovirus and coagulopathy in pig-to-primate xenotransplantation.

BACKGROUND: A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC. METHODS: Endothelial activation was assessed by means of measurement of porcine tissue factor (pTF) in a functional assay in primary porcine aortic endothelial cells (PAEC) in vitro. Renal xenografts and native kidneys were studied by immunohistochemistry in immunosuppressed swine and baboons. BCMV and PCMV DNA was measured by quantitative molecular assays using real-time polymerase chain reaction. RESULTS: In vitro, infection of PAEC with PCMV resulted in a significant increase of pTF expression. In vivo, pTF increase occurred without the activation of PCMV in two xenografts, and in four grafts no pTF was detected despite PCMV activation. All animals with graft pTF increase developed CC. BCMV activation in the baboon xenograft recipients did not correlate with CC or pTF increase. Control pigs and baboons had activation of PCMV and BCMV, respectively, but without coagulation abnormalities. CONCLUSIONS: PCMV induces endothelial cell activation in vitro with procoagulant expression. However, in vivo, CC and pTF induction has an uncertain relationship to increased replication of PCMV within a xenograft. Although the data do not exclude a contributory role of PCMV in CC, other mechanisms are also likely to contribute to coagulopathies observed in pig-to-primate xenotransplantation.

Animals↗
PubMed2005

Porcine hematopoietic progenitor cell transplantation in nonhuman primates: a review of progress.

The critical shortage of human donor organs for transplantation would be overcome if a suitable animal, e.g., the pig, could be used as an organ source. There are, however, several immune barriers that have to date resulted in limited function of pig organs transplanted into nonhuman primates. It would be beneficial, and indeed may be essential, to induce a state of tolerance in the primate recipient to the pig organ. In allotransplantation, the successful transplantation of hematopoietic progenitor cells with the development of mixed chimerism is associated with the induction of tolerance toward a donor-specific organ. For some years, this approach has been explored in the pig-to-nonhuman primate model. This experience is briefly reviewed. The problems of natural and elicited anti-pig antibodies, recipient platelet adhesion to pig hematopietic progenitor cells, and the rapid removal of these cells by the host macrophage-phagocytic system are highlighted. Recent experience with the use of hematopoietic cells from pigs homozygous for alpha1,3-galactosyltransferase gene-knockout is reported.

Animals↗
PubMed2006

Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms.

BACKGROUND: CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined. METHODS: Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6). RESULTS: CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy. CONCLUSION: CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.

Animals↗
PubMed1996

Mutations in S-cone pigment genes and the absence of colour vision in two species of nocturnal primate.

Most primates have short-wavelength sensitive (S) cones and one or more types of cone maximally sensitive in the middle to long wavelengths (M/L cones). These multiple cone types provide the basis for colour vision. Earlier experiments established that two species of noctural primate, the owl monkey (Aotus trivirgatus) and the bushbaby (Otolemur crassicaudatus), lack a viable population of S cones. Because the retinas of these species have only a single type of M/L cone, they lack colour vision. Both of these species have an S-cone pigment gene that is highly homologous to the human S-cone pigment gene. Examination of the nucleotide sequences of the S-cone pigment genes reveals that each species has deleterious mutational changes: in comparison to the sequence for the corresponding region of the human gene, exon 4 of the bushbaby S-cone pigment gene has a two nucleotide deletion and a single nucleotide insertion that produces a frame shift and results in the introduction of a stop codon. Exon 1 of the owl monkey S-cone pigment gene likewise contains deletions and insertions that produce a stop codon. The absence of colour vision in both of these nocturnal primates can thus be traced to defects in their S-cone pigment genes.

Amino Acid Sequence↗
PubMed1977

Replication of enterovirus 70 in non-primate cell cultures.

Replication of the strain J 670/71 of enterovirus 70 (EV70) in non-primate cell cultures at 33 degrees C was studied using strain L (mouse), BHK21 (hamster), RK13 (rabbit), RK17 (rabbit), PK15 (porcine), IB-RS-2 (porcine), ESK (porcine), MDBK (bovine), and BK1 (primary bovine) together with that of the LSc, 2ab strain of poliovrus type 1 (PV1) as a control. All the cells tested adsorbed from 54 to 90% of EV70. The replication with complete c.p.e. was evident in RK13, RK17 and BK1 cells; replication without c.p.e. was shown in L, BHK21, IB-RS-2 and ESK; but PK15 and MDBK were non-permissive despite a high virus adsorption rate. On the contrary, none of these non-primate cells allowed the adsorption and growth of PV1. One-step growth of EV70 in RK13 was almost identical with that in the primate cells. Two other strains of EV70 were found having similar host range in vitro. Therefore, it is concluded that EV70 has a wider host range in vitro than ordinary human enteroviruses, and its implication is discussed.

Adsorption↗