Intraocular ovarian isografts in female rats and their response to gonadotropins and to pituitary isografts.
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Substance P and vasoactive intestinal peptide in rat small-bowel isografts.
BACKGROUND: It is established that substance P (SP) is released by stimulation of nonadrenergic noncholinergic (NANC) excitatory nerves and vasoactive intestinal peptide (VIP) by stimulation of NANC inhibitory nerves. To evaluate the function of peptidergic nerves such as SP and VIP in small-bowel isografts, we examined the enteric nerve responses to SP and VIP in the isografted rat jejunum, using the normal rat jejunum as a control. METHODS: Orthotopic entire small bowel transplantation (SBT) with portocaval drainage was performed from Lewis rats to Lewis rats. Grafted tissue specimens were obtained 130 days after SBT (n = 9). As controls, normal segments of the jejunum were obtained from untransplanted Lewis rats (n = 22). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the enteric nervous system before and after treatments with various autonomic nerve blockers and neuropeptides (SP and VIP). RESULTS: SP concentration-dependently mediated the contraction reaction of NANC excitatory nerve in the isografted jejunum and to a lesser extent in the normal jejunum. In addition, there were significant diferences in the percentages showing contraction at 1 x 10(-8) and 1 x 10(-6)g/mL SP between the normal and isografted jejunal muscle strips (P < .05, respectively). VIP concentration dependently mediated the relaxation reaction of NANC inhibitory nerve in the normal jejunum and to a lesser extent in the isografted jejunum. In addition, there was a significant difference between the relaxation frequencies of the normal and those of isografted jejunal muscle strips at 1 x 10(-6) g/mL SP (P < .01). CONCLUSIONS: Contraction reactions of SP were observed in both the normal and isografted jejunum but were increased in the isografted jejunum. Relaxation reactions of VIP were also observed in both the normal and isografted jejunum but were decreased in the isografted jejunum. The increase of the effects of SP via NANC excitatory nerves and the decrease of the effects of VIP in mediating NANC inhibitory nerves may be largely related to the peristaltic abnormalities seen in the isografted LEW rat jejunum.
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The effect of allogeneic presensitization on Hya-isograft survival.
The effect of allogeneic presensitization on Hya isograft survival was reinvestigated in C57BL, C3H and (C57BL x C3H)F1 females. Three weeks after transplantation of H-2 or non-H-2 differing female or male skin grafts, a syngeneic male skin graft (Hya isograft) was transplanted onto female recipients. C57BL and (C57BL x C3H)F1 females pretreated with a female skin graft of any origin rejected the C57BL male isograft as a first-set, while females pretreated with a male skin graft rejected the C57BL male isograft in a second-set manner. The same happened with the C3H male skin graft transplanted onto previously challenged (C57BL x C3H)F1 females. C3H females pretreated with a C3H or CBA female graft rejected the C3H male isograft as a first-set, whereas those pretreated with a C3H or CBA male graft rejected the male C3H isograft in a second-set manner. However, after pretreatment with a BALB/c male skin graft, C3H females were not sensitized to Hya. They rejected the C3H male isograft slightly faster than was expected for the first graft but this accelerated rejection was not specific, since it occurred as well in C3H females pretreated with grafts of BALB/c females. The best explanation for this unsuccessful immunization of C3H females is that an inferior, non-H-2-dependent Hya recognition system is involved in male isograft rejection.
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Bilateral native nephrectomy improves renal isograft function in rats.
Bilateral native nephrectomy has been suggested to improve renal allograft survival in man. This effect may be most prominent in patients experiencing acute tubular necrosis following transplantation. Thus, native kidneys may alter the course of ischemic acute tubular necrosis in the transplanted kidney. In the present studies, we utilized an experimental model of syngeneic transplantation in which rejection does not occur. We studied Lewis rat renal isografts transplanted into littermates following sham, unilateral or bilateral native nephrectomy. In a fourth group of rats, we evaluated the importance of native kidney excretory function by studying isografts transplanted into littermates with bilaterally obstructed native kidneys. Renal blood flow and excretory function were measured in vivo, eight days following transplantation. Renal excretory function of isografts transplanted into animals following bilateral native nephrectomy was similar to normal nontransplanted Lewis kidneys. The presence of either one or both functioning native kidneys significantly reduced isograft inulin clearance, PAH clearance, and blood flow. However, when isografts were transplanted into Lewis rats with bilaterally obstructed native kidneys, renal isograft inulin clearance and blood flow were not significantly impaired. Nontransplanted kidneys demonstrated "functional hypertrophy" following contralateral nephrectomy, with glomerular filtration rate and renal blood flow increasing by approximately 50%. In contrast, isograft glomerular filtration rate in animals following bilateral native nephrectomy was equivalent to that of single kidneys from normal animals with both kidneys in situ. However, renal blood flow of isografts from these animals increased to the same level as nontransplanted Lewis kidneys following contralateral nephrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)
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Kinetics of mammary epithelial cell proliferation in pituitary isografted BALB/c mice.
Recently, we have published that treatment of pituitary isografted BALB/c mice with a single injection of N-methyl-N-nitrosourea (MNU) leads to the rapid development of mammary tumors in over 90% of the animals (Guzman et al., Cancer Res., 52, 5732-5737). In the present study, we characterized the changes in proliferative activity and lobulo-alveolar differentiation of MECs at different time intervals after isografting animals with pituitary glands. Virgin BALB/c mice 1, 3, 5 or 8 weeks after pituitary isografting were either pulse-labeled for 2 h or continuously infused with bromodeoxyuridine (BrdU) and the percentage of BrdU-labeled MECs was assessed. The S-phase duration (TS) of MECs was evaluated by double labeling with [3H]thymidine and BrdU. The population potential doubling time (TP) was calculated from the values of BrdU-LI and TS. Three stages of proliferation and differentiation of MECs in pituitary isografted virgin BALB/c mice were observed: (i) A sharp increase in the percentage of proliferating MECs of the terminal ducts and ductal branchings in the first 1-2 weeks, (ii) Development of lobulo-alveolar structures from the terminal ductal and alveolar buds, between weeks 3 and 5 with the highest BrdU-LI in week 3 and (iii) Multiplication of the alveolar structures and decrease in the BrdU-LI between weeks 5 and 8. The BrdU-LIs of alveolar cells 5 weeks after isografting the animals were significantly higher than those of the ductal cells. The continuous administration of BrdU for 3, 5 or 7 days by using osmotic pumps revealed zones in the ducts where almost all MECs were labeled as well as zones lacking proliferate activity. When the BrdU administration was extended for 10-14 days, almost all (> 95%) ductal and lobular epithelial cells were labeled. A small percentage (< 5%), of ductal and lobulo-alveolar MECs cells, remained unlabeled even after 14 days infusion of BrdU. The TS and TP values were shorter in pituitary isografted animals than in controls, but no significant difference was found for either values between the ductal and alveolar cells in either isografted or control mice. Changes in proliferation kinetics of mouse MECs in pituitary isografted animals correlated with the circulating concentrations of prolactin, progesterone and 17 beta-estradiol, but not with corticosterone, growth hormone or thyroxin.(ABSTRACT TRUNCATED AT 400 WORDS)
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Male skin isografts can induce unresponsiveness in female rats.
Nonsensitized (DA x PVG/c) F1 hybrid female rats regularly accepted male skin isografts. However, almost all F1 females sensitized with male F1 bone marrow cells rejected male skin isografts. Spleen cells taken from sensitized F1 females, either before or after the rejection of male skin isografts, conferred resistance against graft-versus-host (GVH) reactions produced in F1 females by parental PVG/c lymph node cells, but only when the cell donors were male. Repeated injection with bone marrow cells from F1 males failed to cause rejection of established male skin grafts by F1 females. Additional male skin grafts transferred after bone marrow cell injection were also retained. However, if established male skin isografts had been deliberately removed from F1 females before injection of male bone marrow cells, subsequently placed male skin grafts were rejected. Neither spleen cells collected from F1 females bearing established male skin isografts after repeated injection with male bone marrow cells, nor spleen cells obtained from F1 females that had received four consecutive male skin isografts were observed to confer resistance against GVH reactions produced by male PVG/c lymph node cells in F1 female recipients. Splenectomy of prospective F1 female recipients did not confer on them the capacity to reject male skin isografts. These results imply that the placement of a male skin isograft interfered with subsequent attempts to stimulate F1 hybrid females to reject male grafts and to resist GVH reactions produced by lymphocytes from PVG/c males.
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Physiologic studies on nitric oxide in rat small bowel isografts.
The enteric nervous system (ENS), especially the nonadrenergic noncholinergic (NANC) inhibitory nerves, is an important factor in intestinal peristalsis. Recently, it was established that nitric oxide (NO) is released after stimulation of NANC inhibitory nerves. Inhibitory nerves such as NANC inhibitory nerves in the ENS are more easily damaged than excitatory nerves by reperfusion or ischemic injuries during small bowel transplantation (SBT). To evaluate the effects of reperfusion and ischemic injuries to the ENS in the transplanted small bowel, we examined the ENS responses, including the effects of NO in the isografted rat jejunum, using the nontransplanted jejunum as a control. To avoid potentially confounding immune phenomena, we used syngeneic Lewis (LEW) rats. Orthotopic entire SBT with portocaval drainage was performed from LEW rats to LEW rats. Isografted muscle strips were obtained from 8 LEW rats 130 days after SBT (n = 24). As controls, normal muscle strips of the jejunum were obtained from 20 nontransplanted LEW rats (n = 60). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, N(G)-nitro-Ll-arginine ( L-NNA), and L-arginine. The results indicated that excitatory nerves, especially NANC excitatory nerves, were more dominant in the isografted jejunum than in the normal jejunum (p < 0.01). NANC inhibitory nerves were found to act on the normal jejunum and to a lesser extent on the isografted jejunum (p < 0.05). NO mediates the relaxation reaction of NANC inhibitory nerves in the normal jejunum and to a lesser extent in the isografted jejunum. These results indicated that the intrinsic intestinal innervation contains excitatory and inhibitory nerves and that the former, especially NANC excitatory nerves, are more dominant in the isografted jejunum than in the normal jejunum. In addition, reduction of the action of NANC inhibitory nerves such as that by NO may be largely related to impaired motility in the isografted jejunum. Thus over a long period of time (more than 130 days after SBT) transplanted small bowel dysmotility may be influenced by reperfusion or ischemic injury to the ENS (especially NANC inhibitory nerves) via NO in the transplanted jejunum after syngeneic SBT.
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Pituitary-isografted mice are highly susceptible to MNU-induced mammary carcinogenesis irrespective of the level of alveolar differentiation.
We have recently developed a mammary tumorigenesis system in which adult female BALB/c mice are grafted with two pituitaries from isologous donors and subsequently treated with a single i.v. injection of N-methyl-N-nitrosourea (MNU, 50 mg/kg). Mice bearing isografts have elevated serum titers of prolactin and progesterone which act on the mammary glands to produce a highly differentiated morphology resembling that of late pregnancy. MNU treatment of the mouse mammary gland in this differentiated state results in tumors in > 90% of tested animals. Since the mammary gland is believed to be particularly vulnerable to chemically induced carcinogenesis during alveolar morphogenesis, we chose to assess the susceptibility of the mammary gland during the initial weeks after pituitary isografting when they are ostensibly undergoing marked cell proliferation and differentiation. To this end, mice were isografted with pituitaries and subsequently analyzed at 1, 3, 5, 8 and 12 weeks for epithelial cell differentiation and susceptibility to MNU-induced tumorigenesis. By 3 weeks after isografting, the glands showed marked lobuloalveolar development and highest casein production. Tumor latency and frequency paralleled parenchymal differentiation for the first 3 weeks. By 5 weeks, and thereafter, the mice continued to be extremely susceptible to MNU-induced mammary carcinogenesis despite the highly differentiated state of the glands. Since tumors generated in this system are not dependent on pituitary isografts for their growth when transplanted to isologous recipients, and since the pituitary isograft does not act as a classical promoter but is required at the time of carcinogen treatment, we conclude that the pituitary isograft maintains a condition permissive for transformation to occur and a level of proliferation sufficient for the expression of the transformed phenotype.
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Expression of fibronectin splicing variants in organ transplantation: a differential pattern between rat cardiac allografts and isografts.
Allograft rejection is associated with infiltration of inflammatory cells and deposition of extracellular matrix proteins. The extent to which diversity in the extracellular matrix regulates inflammatory cell function in transplants remains unclear. One group of extracellular matrix proteins, termed fibronectins (FNs), exhibits inherent diversity as a consequence of alternative splicing in three segments: EIIIA, EIIIB, or V. Although the EIIIA segment has documented functions in mesenchymal cell differentiation, neither this segment nor the EIIIB segment have been tested for effects specific to leukocyte functions. By contrast, the V region can include the CS-1 segment to which leukocytes may adhere through alpha 4 beta 1 integrins. In this study, we demonstrate that EIIIA+, EIIIB+, and V+ FN variants are synthesized, primarily by macrophages in distinct temporal and spatial patterns in two rat cardiac transplant models: either with antigenic challenge, allografts, or without challenge, isografts. The ratio of EIIIA inclusion into FN increases by day 1 in allografts and isografts and remains high until allografts are rejected (approximately 7 days) but falls to normal levels in tolerated isografts (day 6). EIIIB+ FN ratios in allografts peak later than do EIIIA+ FNs (day 4). EIIIB+ FN ratios remain relatively low in isografts. Interestingly, EIIIA+ and EIIIB+ FNs are deposited prominently in the myocardium of rejecting allografts in close association with infiltrating leukocytes, and FN expression and deposition are prominent at sites of infarction. By contrast, these FNs are largely restricted to the epicardium and to a lesser degree in the immediately adjacent myocardium in isografts. CS-1+ FNs increase in allografts and isografts at 3 hours after transplantation but are particularly prominent in allografts 1 to 3 days before rejection. Our data suggest that FN splicing variants have a differential role in the effector functions of leukocytes in allografts and isografts and provide a foundation for testing their function on leukocytes and a rationale for FN-based therapeutics to modulate allograft rejection in transplant recipients.
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Cold ischemia induces isograft arteriopathy, but does not augment allograft arteriopathy in non-immunosuppressed hosts.
Prolonged cold ischemia has been suggested as a factor that will exacerbate later graft arterial disease (GAD), a major limiting factor for long-term transplant survival. We therefore examined the effects of cold ischemia on GAD as well as adhesion molecule and cytokine expression in murine cardiac grafts. Mild GAD developed in isografts undergoing 4-hour cold ischemia. Relative to control isografts, cold ischemia induced transiently enhanced endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at 4 hours post-transplant. There was also transiently-augmented gene expression of interleukin (IL)-1beta, IL-6, and transforming growth factor-beta in these cold-ischemic isografts. By 3 days post-transplantation, however, there were no longer any differences between control and cold ischemic isografts. Cold ischemia did not significantly affect the final grade of either parenchymal rejection or GAD in long-term (4 to 12 weeks) major histocompatibility complex (MHC) I- or MHC II-mismatched allografts molecules transplanted without immunosuppression. At early time points after cold ischemia (4 to 24 hours), allografts mismatched for MHC I and/or MHC II showed enhanced expression of ICAM-1 and cytokines comparable to that seen in isografts. By day 7 post-transplant, both control and cold ischemia allografts showed comparable expression of cytokines and adhesion molecules. Although prolonged cold ischemia can initiate mild GAD in isografts by transiently enhancing antigen non-specific inflammatory responses, it does not significantly augment subsequent alloresponses.
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Limit of warm ischemia time before cryopreservation in rat tracheal isografts.
BACKGROUND: The viability of cadaveric tracheal grafts undergoing cryopreservation is still unclear. We evaluated the limit of warm ischemia time before cryopreservation in rat tracheal isografts. METHODS: Each isograft was harvested from donor rats 0 to 48 hours (0, 6, 12, 18, 24, and 48 hours) after circulatory arrest, immersed in the preservative solution, and stored in a deep freezer until reaching -80 degrees C and then was kept in liquid nitrogen for 3 months. Heterotopic transplantation into the omentum was performed after the isografts were thawed. Graft morphology 3 months after transplantation was assessed. RESULTS: The stepwise increase of warm ischemia time significantly reduced graft survival. A prolonged period of warm ischemia had a degenerative effect on both the epithelium and cartilage. The morphology of the epithelium and cartilage in isografts undergoing warm ischemia for less than 18 hours was better preserved, whereas it deteriorated in isografts undergoing warm ischemia for more than 24 hours. CONCLUSIONS: We thus conclude that the permissible period of warm ischemia before 3-month cryopreservation to maintain tracheal isograft viability is 18 hours in rats.
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Maximal period of cryopreservation with the Bicell biofreezing vessel for rat tracheal isografts.
OBJECTIVE: The maximal period of cryopreservation for the trachea is still unsolved. We assessed the maximal period of cryopreservation using the Bicell biofreezing vessel as an easy and cheap slow-freezing instrument for viable tracheal grafts in 95 rats. METHODS: Each isograft was harvested from 17 donor rats, immersed in the preservative solution, and stored in a Bicell device in a deep freezer at -80 degrees C. The tracheal isografts were then randomly assigned to 9 groups according to cryopreservation periods ranging from 0 to 12 months. Included in the 9 groups were 2 subgroups (n = 6 per subgroup) that were observed immediately after being thawed and 1 month after heterotopic transplantation into the omentum after being thawed. Four subgroups (n = 6 per subgroup) were added according to the cryopreservation period for 1, 3, 6, and 12 months to evaluate the graft morphology 3 months after being thawed and transplanted heterotopically. RESULTS: A prolonged period of cryopreservation had a degenerative effect on both the epithelium and cartilage. One month after transplantation, degeneration was more pronounced in the cartilage than in the epithelium, as characterized by the viable chondrocyte ratio and the epithelial score of isografts undergoing cryopreservation for more than 9 months. Three months after transplantation, the morphology of the epithelium and cartilage in isografts undergoing cryopreservation for less than 3 months was better preserved, whereas the morphology of both deteriorated in isografts undergoing cryopreservation for more than 6 months. CONCLUSIONS: We conclude that the permissible period of cryopreservation to maintain tracheal isograft viability in this simple system using a Bicell biofreezing vessel is 3 months.
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Cell proliferation and apoptosis during mammary carcinogenesis in pituitary isografted mice.
In the present study, pituitary isografted animals serve as a model for evaluating the changes in differentiation, cell proliferation and programmed cell death (apoptosis) in mammary epithelial cells during carcinogenesis. The percentage of bromodeoxyuridine (BrdU)-labeled ductal and alveolar cells was significantly higher in pituitary isografted animals than in non-isografted control animals. BrdU-labeled cells increased in lobular hyperplastic nodules, keratinized nodules and mammary carcinomas; similar changes were observed with apoptotic cells, which were rare in mammary glands of adult non-isografted animals (one to three apoptotic cells per 2000 mammary epithelial cells), but their number increased in hyperplastic lesions and mammary carcinomas. Among hyperplastic nodular lesions, variants with high, moderate and low proliferative activity and/or apoptotic cell death were identified, which suggests that they may have different growth potentials and different propensities for malignant transformation. After removing pituitary isografts, apoptosis occurs in hyperplastic lesions but not in mammary carcinomas-implying that malignant tumors are hormone-independent. The dynamics of the changes in apoptotic cell death among various hyperplastic lesions after removal of pituitary isografts suggests that these lesions are composed of heterogeneous cell populations, as far as the initiation of apoptosis is concerned. Our data indicate that apoptosis can be used together with cell proliferation as a potential marker in characterizing the growth potential and phenotypic diversity of hyperplastic, premalignant and malignant mammary gland lesions.
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Effect of STZ administration on islet isograft and allograft survival in NOD mice.
We examined the effect of a single STZ administration on subsequent islet isograft and allograft survival in NOD mice. Young prediabetic NOD mice were rendered diabetic by STZ administration and transplanted with islet isografts 8-11 days later. The earliest loss of islet function occurred on postgraft day 49. In sharp contrast, 15 of 16 isografts in spontaneously diabetic mice were destroyed within 17 days postgrafting. A comparison of the age of islet isograft destruction in STZ-induced diabetic NOD mice with the course of diabetes development in the NOD mouse colony clearly showed that STZ administration at the prediabetic stage led to a significant delay of diabetes onset in isografts. When STZ was given to overtly diabetic NOD mice, both islet isografts and allografts survived significantly longer than those in untreated, spontaneously diabetic NOD mice. However, the degree of prolongation induced by STZ was much smaller compared with that induced by ALS, a potent immunosuppressive reagent. In vitro mixed lymphocyte culture experiments showed that spleen cells of mice given STZ exhibited time-dependent reduction of their alloantigen reactivities. These results demonstrate that STZ, which is commonly used to induce diabetes in various experimental animals, also possesses an immunosuppressive property, although it is relatively weak compared with ALS.
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Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat.
Islet transplantation for the treatment of autoimmune diabetes is more difficult because of the additional barrier presented by the autoimmunity. We tested the ability of hamster anti-rat CD154 to prevent recurrence of diabetes in renal subcapsular islet isografts in DR-BB (RT1uu) rats with established autoimmune diabetes. Experimental animals with established diabetes received intravenous injections of 15 mg/kg anti-CD154 on a specified schedule starting 2 days before renal subcapsular transplantation of an islet isograft. Control animals received either saline or hamster IgG. Plasma glucose levels >250 mg/dl over 3 days were used to indicate the recurrence of diabetes. Rats that received saline (n = 5) or control antibody (n = 3) had a recurrence of diabetes 6-11 days after transplantation. Histological examination of islet isografts from these rats showed complete destruction of the insulin-producing portion of the isograft with residual cells positive for glucagon. Recipient rats that received anti-CD154 at the 15-mg/kg dosage (n = 6) did not have a recurrence of diabetes for 308-461 days after transplantation. Islet isografts removed from the rats showed low levels of insulin immunoreactivity, high levels of insulin mRNA, and focal infiltration with lymphocytes but no evidence of islet destruction. Mean peak antibody concentration was 266 microg/ml and returned to undetectable levels by 67-88 days after transplantation. Rats that received anti-CD154 starting at 4-7 days after transplantation had a recurrence of diabetes within 11 days of the isotransplantation. Therefore, anti-CD154 as the sole immunomodulator prevented the recurrence of diabetes in islet isografts in rats with established autoimmune diabetes. This suggests that CD40/CD154 blockade is effective in preventing the insulitis or the effector phase of autoimmune diabetes.
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Quantitative assessment of angiogenesis and osteogenesis after transplantation of bone: comparison of isograft and allograft bone in mice.
We performed a vital microscopic study in mice bearing dorsal skinfold chambers to characterize microvascular perfusion and leukocyte/endothelium interaction and their effects on elongation and mineralization of neonatal isograft and allograft bone. Isograft (C57/BL to C57/BL) and allograft bone (C57/ BL to BALB/C) revascularized simultaneously. However, vascular perfusion and density were lower in allograft bone than in isograft bone. Leukocyte/endothelium interaction was the same in isograft and allograft bones. Revascularization was not detected in allograft bone transplanted to presensitized recipients. Moreover, in preexisting vessels at the transplantation site, leukocyte/endothelium interaction was altered in allograft bone of presensitized recipients, despite a normal systemic leukocyte count. Femoral growth resulting from thickening of both epiphyses did not differ between experimental groups, however, mineralization occurred in isograft bone only. Isograft bone was histologically intact, allograft bone hypovital and allograft bone in presensitized recipients necrotic 12 days after implantation. Our findings suggest that graft incorporation or rejection is mediated by the microvasculature and that presensitizing of recipients accelerates rejection of allograft bone.
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Lymphocyte entry into inflammatory tissues in vivo. Qualitative differences of high endothelial venule-like vessels in sponge matrix allografts vs isografts.
Sponge matrix allografts and isografts become extensively encapsulated and neovascularized after s.c. implantation. Sponge allografts acquire alloantigen-reactive T lymphocytes, whereas sponge isografts fail to do so, even though these T cells are continuously circulating in the peripheral blood. We have investigated the possibility that the vascular endothelia regulates lymphocytic accumulation in sponge matrix implants. In normal lymph nodes, specialized high endothelial venules (HEV) regulate lymphocyte extravasation from the blood. We have now identified HEV-like vessels in sponge matrix allografts. These vessels are operationally defined as "HEV-like" in that they react with mAb MECA 325 which identifies murine HEV, and bind lymphocytes in ex vivo adhesion assays. In contrast, sponge isografts contain MECA 325 reactive vessels that are significantly smaller than those found in allografts. Further, vessels of sponge isografts do not readily bind lymphocytes in ex vivo adhesion assays. Immunohistologic analysis also revealed that the small MECA 325+ vessels present in sponge isografts are consistently found in close proximity to nerve bundles. Although this MECA 325 reactive vessel-nerve bundle association is also observed in sponge allografts, large MECA 325 reactive vessels are widely distributed in allografts. Our data suggest that small, poorly adhesive MECA 325 reactive vessels develop in sponge isografts and allografts, possibly under the influence of local nerve tissue. These vessels respond to regional alloimmune responses by developing into the larger HEV-like vessels capable of binding lymphocytes in sponge allografts. The value of this experimental system as an in vivo model to evaluate mechanisms involved in neovascularization and endothelial differentiation is discussed.
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In situ localization of prolactin receptor message in the mammary glands of pituitary-isografted mice.
The receptors for prolactin (PRLR) are expressed in many tissues including the mammary gland, a classical target tissue for prolactin (PRL), but the cellular localization of expression of the PRLR gene in mammary gland has not yet been identified. PRL is known to up regulate its own receptor. We therefore employed the pituitary isografted mouse as a model to distinguish the cells expressing PRLR since PRL blood levels are known to be constitutively elevated in these animals. Mammary glands of virgin or pituitary isografted mice were analyzed by northern blot or in situ hybridization with a digoxygenin-labeled cRNA probe. Northern analysis revealed the expression of 1.3 kb and 2.5 kb forms of PRLR corroborating the results of various laboratories studying other tissues. PRLR was barely detectable by in situ hybridization in non-isografted mice. Two weeks after pituitary isografting, however, PRLR expression was substantially increased in the epithelial cells of mammary ducts and alveoli. No signal was ever detected in the mammary stromal compartment of either virgin or pituitary-isografted mice. The localization of PRL-responsive cells to the parenchyma of the mammary gland suggests that epithelial cells are the mediators of PRL action and that the transcriptional regulation of PRLR expression by PRL is direct in the epithelial cell.
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