Use of a murine xenograft model for canine transmissible venereal tumor

OBJECTIVE: To develop a murine model for canine transmissible venereal tumor (CTVT). ANIMALS: Thirty-three 6-week-old NOD/LtSz-scid (NOD/SCID) mice and seven 6-week-old C57BL/6J mice. PROCEDURE: Samples of CTVT were excised from a 3-year-old dog and inoculated SC into ten 6-week-old NOD/SCID mice to induce growth of xenograft transmissible venereal tumor (XTVT). To establish mouse-to-mouse transmission, samples of XTVT were removed and inoculated SC into 4 groups of 6-week-old NOD/SCID mice and into a control group. Samples of CTVT were also inoculated into immunocompetent C57BL/6J mice for a mouse antibody production (MAP) test. The canine and xenografted tumors were evaluated cytologically and histologically, and polymerase chain reaction was performed for detection of the rearranged LINE/c-MYC junction. RESULTS: 8 of 10 NOD/SCID mice that were inoculated with CTVT developed tumors 3 to 10 weeks after inoculation. In the second-generation xenograft, all mice developed tumors by postinoculation day 47; 1 X 10(6) of XTVT cells were enough to create a xenograft. Metastases developed in 4 of 20 mice. Xenografted and metastatic tumors retained cytologic, histologic, and molecular characteristics of CTVT. Results of the MAP test were negative for all pathogens. CONCLUSION: We established an NOD/SCID murine model for XTVT and metastasis of CTVT. This model should facilitate study of tumor transplantation, progression, and metastasis and should decrease or eliminate the need for maintaining allogenic transfer in dogs.     

Long term substitution and specific immune responses after transfer of bovine peripheral blood lymphocytes into severe combined immunodeficient mice.

The long term immune responsiveness of bovine peripheral blood lymphocytes engrafted into severe combined immunodeficient mice (bovine PBL SCID mice) was analyzed. After intraperitoneal transfer (i.p.) of 2x10(7) bovine PBL into SCID mice, FACS analysis revealed successful engraftment of bovine CD4 and CD8+ T cells in the peritoneal cavity, the peripheral blood, spleen, lymph nodes, bone marrow, and thymus of reconstituted mice for up to 13 weeks. As shown by immunocytochemistry in sections of spleens from SCID mice 16 weeks after substitution, bovine T and B cells were localized perivasculary forming pseudofollicular structures. Nevertheless, histopathology of spleen and liver from bovine PBL SCID mice revealed pathological alterations indicating rejection of xenogenic cells or graft versus host disease (GVHD). On the functional level, i.p. transfer of bovine PBL into SCID mice induced increasing levels of bovine IgM and IgG in the sera of recipients. Bovine Ig could be detected up to 20 weeks. Immunization of SCID mice reconstituted with PBL of normal donors with dinitrophenol (DNP)-edestin induced a weak specific bovine antibody response in recipient mice. In contrast, a secondary specific bovine IgG response was observed after antigen restimulation of SCID mice reconstituted with PBL from calves preimmunized either with DNP-edestin or keyhole limpet hemocyanin (KLH) showing functional T cell-independent and -dependent antibody responses of bovine PBL SCID mice. Our data demonstrate that transfer of bovine PBL into SCID mice leads to a long term engraftment of bovine cells in lymphatic and non-lymphatic organs inducing a functional substitution of T and B cell immune response of SCID mice. Therefore, bovine PBL SCID chimera can serve as a small animal model for the analysis of bovine lymphopoiesis and infectious diseases of cattle.     

Infectivity and pathological changes in murine clonorchiasis: comparison in immunocompetent and immunodeficient mice

The main complications of clonorchiasis are periportal inflammation, biliary hyperplasia, periductal fibrosis, and subsequently the development of biliary tumors in the liver. This study was undertaken to compare the infectivity and histopathologic changes between in immunocompetent FVB/NJ and BALB/cA strains, and immunodeficient severe combined immunodeficient (SCID) and athymic nude mice after the metacercariae of Clonorchis (C.) sinensis were infected. The experiment showed that C. sinensis was very infective in all strains studies, but the status of worm development, infectivity, recovery rate, and morphological changes of livers were very different in each strain. FVB/NJ mice showed more worm recovery than any other strain. Histopathologically the liver of FVB/NJ mice at 4 weeks postinfection showed marked cystic and fibrotic changes, in which C. sinensis was fully developed with ovum production, severe infiltration of inflammatory cells, mostly eosinophils, and high degrees of biliary hyperplasia. In SCID and nude mice, there were few foci of inflammatory cells even at 8 weeks postinfection in periportal areas of the liver, associated with no development into adult worm with ovum production. Fibrosis occurring at 4 weeks postinfection was highly correlated with inflammatory infiltration when each strain was compared. We suggest that massive infiltration of eosinophil and plasma cells caused by the infection might initiate cystic formation and fibrosis. These data demonstrate that the infection of C. sinensis might be related to pathologic consequences of inflammatory cell infiltration, cystic formation and fibrosis which might play a role in the defense mechanism against the parasitism in the liver of each strain. The FVB/NJ mouse model might be very helpful in elucidating the mechanism for human clonorchiasis.     

Pegylated liposomal doxorubicin as a chemotherapeutic agent for treatment of canine transmissible venereal tumor in murine models

The effectiveness of Doxil as a new chemotherapeutic agent against canine transmissible venereal tumor was evaluated, using NOD/ SCID and CD1-nu xenograft mouse models and the response between the two mouse strains was compared. Samples of xenografted venereal tumor were inoculated SC into 20 six week-old NOD/SCID mice and 20 six week-old CD1-nu mice. Seven weeks later, tumor-bearing mice were divided into treatment and control groups. Treatment group was injected with Doxil (6 mg/kg, IP, as a single injection). Control group was injected with buffered saline (0.75cc, IP). Tumor size was determined by caliper measurements and tumor response was assessed according to standard criteria. In both strains there was a significant decrease in tumor size in response to Doxil treatment (P<0.0001). In CD1-nu eight out of nine tumors (88%) responded to the treatment, and in 2 cases complete remission was observed. In NOD/SCID group response to the treatment was seen in eight out of ten tumors (80%) but none regressed fully. Response to the treatment was statistically equal in both strains even though the apoptotic rate, confirmed by TUNEL staining, was higher in NOD/SCID than in CD-1-nu (8.65% and 0.7%, respectively) and tumor infiltrating cells were different: eosinophils in NOD/SCID and CD45R-positive B lymphocytes, and plasma cells in CD-1-nu. In untreated CD1-nu mice, tumor progress was slower than in NOD/SCID. Our results indicate that Doxil is effective against CTVT in mouse xenograft models.     

Anti‐tumour activity of oncolytic reovirus against canine histiocytic sarcoma cells

Canine histiocytic sarcoma is an aggressive, fatal neoplastic disease with a poor prognosis. Lomustine is generally accepted as the first‐line systemic therapy, although this compound does not provide complete regression. Therefore, research into a novel approach against canine histiocytic sarcoma is needed. However, anti‐tumour effects of oncolytic therapy using reovirus against histiocytic sarcoma are unknown. Here, we showed that reovirus has oncolytic activity in canine histiocytic sarcoma cell lines in vitro and in vivo. We found that reovirus can replicate and induce caspase‐dependent apoptosis in canine histiocytic sarcoma cell lines. A single intra‐tumoural injection of reovirus completely suppressed the growth of subcutaneously grafted tumours in NOD/SCID mice. Additionally, we demonstrated that susceptibility to reovirus‐induced cell death was attributable to the extent of expression of type I interferons induced by reovirus infection in vitro. In conclusion, oncolytic reovirus appears to be an effective treatment option for histiocytic sarcoma, and therefore warrants further investigation in early clinical trials.     

Susceptibility of liver proliferative lesions in heterozygous p53 deficient CBA mice to various carcinogens

To investigate the liver tumorigenic sensitivity to various carcinogens in heterozygous p53 deficient [p53 (+/-)] CBA mice and their wild-type littermates [p53 (+/+) mice], 71 p53 (+/-) and 74 p53 (+/+) CBA mice (male, 6-12 weeks of age) were given diet containing 4,000 or 0 ppm flumequine (FL) for 26 weeks or a single intraperitoneal injection of 5 mg/kg body weights dimethylnitrosamine (DMN) at start of the study in Exp. 1, diet containing 6,000 or 0 ppm di(2-ethylhexyl)-phthalate (DEHP) for 26 weeks in Exp. 2, or diet containing 12,000, 6,000 or 0 ppm phenolphthalein (PhP) for 26 weeks in Exp. 3. All surviving animals of these groups were killed after completion of treatment of the test substances for 26 weeks. In the FL groups, the incidences of hepatocellular altered foci in p53 (+/-) mice, the multiplicities of those in p53 (+/-) and p53 (+/+) mice were significantly increased as compared to the corresponding control groups. The incidences and multiplicities of altered foci in the DMN groups were higher than those in the corresponding control groups in p53 (+/-) and p53 (+/+) mice, but no significant differences were indicated between the groups. There were no significant differences in the incidences, multiplicities and proliferating cell nuclear antigen labeling indices of altered foci in the FL or DMN groups between p53 (+/-) and p53 (+/+) mice. There were no significant differences in the incidences and multiplicities of altered foci between the DEHP or PhP and control groups. The present results suggest that p53 gene knocked out heterozygously does not enhance the chemical hepatocarcinogenesis in CBA mice.     

A syngeneic hepatocellular carcinoma model rapidly and simply prepared using a hydrodynamics-based procedure

A rapid and simple method to deliver tumor cells into the liver by intravenous injection of a large volume of tumor cell solution at a high velocity has been developed for use in the preparation of hepatic cancer mouse models. With this hydrodynamics-based procedure, there was a 100% tumor occurrence in the liver and lungs of mice at 2 and 3 weeks, respectively. In contrast, mice injected using a non-hydrodynamics-based system showed no tumor occurrence in the liver 3 weeks after injection, although tumors were present in the lungs. The technique may be useful in the rapid development of hepatic cancer mouse models and in reducing animal mortality during model preparation.     

Cetacean-reconstituted severe combined immunodeficient (SCID) mice respond to vaccination with canine distemper vaccine

Morbillivirus infections have been responsible for mass mortalities in several species of marine mammals. Nevertheless, relatively little is known on the pathogenesis of the disease and the immune response to the agent, especially in cetaceans, hindering the treatment of individuals and the development of appropriate vaccines, given the difficulty of performing experimental work in marine mammals. The reconstitution of severe combined immunodeficient (SCID) mice, which do not have the ability to reject grafts, with lymphocytes from different species has been used with increasing success as a surrogate species model to study the immune system. We injected NOD/SCID mice with lymphocytes from different species of cetaceans and further vaccinated those mice with a commercial canine distemper virus (CDV) vaccine to develop a practical model to study cetacean immune response to a morbillivirus. Reconstitution was detected in 10/20 mice reconstituted with harbor porpoise spleen, 6/10 mice reconstituted with harbor porpoise lymph node cells, 8/10 mice reconstituted with fresh beluga PBMCs and none of the mice reconstituted with neonate bottlenose dolphin spleen or thymus cells when assessed 42-63 days after reconstitution. While a humoral immune response was detected in none of the reconstituted mice, a cell-mediated immune response to the CDV vaccine was detected in 6/15 (40%) and 2/18 (11%) of the SCID mice after reconstitution with cetacean immune cells after a single or booster vaccination, respectively, for a combined total of 8/33 (24%). This represents the first demonstration of successful reconstitution of SCID mice with marine mammal cells, and to the authors' knowledge, the first direct demonstration of a primary antigen-specific cell-mediated immune response in reconstituted SCID mice. This model will be useful for further research on the physiology of the marine mammal immune system and its response to infectious agents and vaccines, with possible important outcomes in conservation issues.     

不同剂量环磷酰胺对昆明小鼠肝肾组织的损伤作用研究

为研究不同剂量的环磷酰胺对小鼠肝肾组织及功能的损害程度,试验选取40只5周龄健康雌性昆明小鼠,随机分为5组,除对照组外,其余4组小鼠连续3 d分别腹腔注射40、80、120及160 mg/（kg·BW）环磷酰胺溶液,注射后第7天采集肝脏和肾脏组织样品及血清,制备石蜡组织切片及透射电镜切片,观察肝脏和肾脏的组织学变化,检测血清中甘胆酸（CG）、胆碱酯酶（ChE）、血清前白蛋白（PA）、总胆汁酸（TBA）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、尿素氮（BUN）、血清肌酐（SCr）、尿酸（UA）含量/活性。结果显示,环磷酰胺可引起小鼠肝肾组织病理损害,呈剂量依赖性,肝脏比肾脏更早出现损伤。石蜡切片及透射电镜切片观察结果显示,环磷酰胺对肝脏的毒性作用主要表现在肝索紊乱、肝血窦扩张、微胆管淤胆、门管区及中央静脉周围炎性细胞浸润及纤维增生、组织间出血、肝细胞出现脂肪变性及气球样变性,凋亡及坏死细胞增多。肾脏组织损伤主要表现在出血及纤维增生,肾小管上皮细胞胞浆空泡样变、线粒体损伤、核固缩,上皮细胞基底膜增厚。环磷酰胺对膀胱的损害不严重。与对照组相比,40~160 mg/（kg·BW）剂量组小鼠血清中ChE活性及PA水平,120~160 mg/（kg·BW）剂量组AST活性,80~160 mg/（kg·BW）剂量组BUN水平及80 mg/（kg·BW）剂量组UA水平均显著升高（P<0.05）;其余生化指标与对照组差异不显著（P>0.05）。以上结果表明,环磷酰胺注射剂量在80~120 mg/（kg·BW）时可引起昆明小鼠肝脏和肾脏组织及细胞明显的病理损伤。该研究结果可为选择合适的环磷酰胺注射剂量用以制备动物肝脏免疫抑制模型提供试验依据。     

Sex difference feeding behaviour of NOD SCID mice in a pharmacological model of type 1 diabetes

This study aimed to assess the sex differences in the feeding behaviour of non-obese diabetic severe combined immunodeficient (NOD SCID) mice in a pharmacological model of type 1 diabetes mellitus (T1Dm). In our study, we chose NOD SCID mice of both sexes and assessed their feeding behaviour, body weight, body fat and water content under identical experimental conditions and diets. After 1 month of diabetes mellitus in mice in the experimental group, males and females did not show any increase in body weight, and they weighed significantly less than the control group. However, compared with the control group, in females with a background of T1Dm, there was a significant decrease in body fat. The amount of water consumed in the experimental groups was higher than that in the control groups. The amount of food consumed by males increased when they increased their water consumption, whereas food consumption in females decreased significantly with an increase in water consumption. Thus, we discovered sex differences in the feeding behaviour, body weight and body fat and water content in the pharmacological model of T1Dm after 1 month in NOD SCID mice.     

Reconstitution of primary, severe, combined immunodeficiency in man and horse

Severe combined immunodeficiency disease (SCID) in foals is the only known animal model for the autosomal recessive form of primary SCID in man. A major requirement in the treatment of SCID is the maintenance of the patient in a disease free state until definitive therapy can be undertaken. This paper reviews the current status of prophylactic and definitive therapy in man and the horse. Particular emphasis is placed on the methods of reconstitution available, involving foetal tissues and bone marrow.     

A pregnant mouse model for bovine Tritrichomonas foetus infection

The economically important effects of Tritrichomonas foetus infection in cattle are abortion and infertility, yet there has not been an animal model to examine the parasite-host interactions during gestation. In this study, 5- and 7- to 8-week-old BALB/cAnNCr, BALB/cJ, and SCID/NCr mice on a BALB/c background were intravaginally infected with T. foetus. All BALB/cAnNCr and BALB/cJ mice, and 89% of SCID/NCr mice sustained infections for 13 weeks, if inoculated before 5 weeks of age. Infection rates were lower in all mouse strains inoculated at 7 weeks of age, although BALB/cAnNCr mice were significantly more susceptible than BALB/cJ or SCID/NCr mice. Vaginal bacterial flora did not account for the variation in mouse-strain susceptibility, although coagulase-negative staphylococci in vaginal flora were associated with failure of T. foetus to infect. As with infected cattle, T. foetus-specific vaginal immunoglobulin (Ig) G and IgA antibodies were elevated after infection. The number and viability of day-10 fetuses were reduced in mice infected at 5 weeks of age and bred 12 weeks after infection. Lesions in pregnant and nonpregnant infected mice, including suppurative and eosinophilic vaginitis; cervicitis; endometritis with distension of the uterine lumen; endometrial ulceration; and glandular ectasia, with neutrophils in the glandular lumen and loss of gland epithelium, were similar to those in cattle. The decidua and placenta were multifocally necrotic. Immunohistochemistry demonstrated trichomonads in vaginal folds and uterine glands, and adjacent to fetal tissues. In summary, experimentally infected BALB/cAnNCr mice showed many pathologic similarities to cattle and may serve as a model to study host-trichomonad interactions.     

Mild hepatic fibrosis in cholesterol and sodium cholate diet-fed rats

To date, the majority of research on hypercholesterolemia has focused on the effects of a high cholesterol diet on atherosclerosis and coronary heart disease. The toxic effects of cholesterol on the liver and the relationship between the intake of a high cholesterol diet and hepatic fibrosis, however, have not been investigated clearly or histopathologically. Male Wistar rats were fed a diet supplemented with 1.0% cholesterol and 0.3% sodium cholate for 12 weeks. Rats were sacrificed and analyzed via blood biochemistry, traditional microscopy and immunohistochemistry. Following the feeding of this diet, the rates of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and total cholesterol in the rats were elevated consistently from week 3 and throughout the remainder of the experiment. From microscopic observation, hepatic necrosis, macrophage infiltration and steatosis increased markedly throughout the experiment. Hepatic fibrosis and myofibroblast proliferation were detected at weeks 9 and 12. Mast cell appearance was proportional to the degree of hepatic damage. These findings suggest that hepatic fibrosis is inducible by a high cholesterol diet and is likely the result of the interaction between several different cell types (i.e., macrophages, myofibroblasts, and mast cells) in an inflammatory milieu. Hypercholesterolemia should be considered as a risk factor for hepatic fibrosis as well as atherosclerosis and coronary artery disease.     

Histopathological changes of the spinal cord and motor neuron dynamics in SOD1 Tg mice

We analyzed the histopathological changes and the number of motor neurons (MNs) in the lumbar spinal cord of Cu/Zn superoxide dismutase transgenic (SOD1^G93ATg) mice, which are frequently used as a disease model of amyotrophic lateral sclerosis (ALS). In SOD1^G93ATg mice, hyaline inclusions and foamy vacuoles in the neuronal cell body were observed at 7 weeks of age before neurologic symptoms, and large vacuoles, spheroid formation, and nerve cell aggregation became prominent after 13 weeks of age. The number of healthy MNs was 28.7 to 37.1 cells/animal in wild-type mice and 9.3 to 13.6 cells/animal in transgenic (Tg) mice. Furthermore, the number of MNs, including degenerative neurons, in Tg mice was 27.3–36.1 cells/animal at 18 weeks of age and 17.8–19.6 cells/animal at 21 weeks of age. The present results provide useful information for the development of drugs in ALS treatment.     

Engraftment of severe combined immune deficient/beige mice with bovine foetal lymphoid tissues.

To develop a model of bovine thymus and lymph node growth in vivo, we have implanted bovine foetal tissues (16-23 weeks gestation) under the renal capsule of severe combined immune deficient (SCID)/beige (BG) mice and assayed for graft growth and characteristics 2-18 weeks after engraftment. Bovine foetal thymus and lymph node grew considerably following engraftment of SCID/BG mice. Growth was optimal if bovine foetal tissues were used before gestation Week 17. Bovine-mouse chimerism was confirmed using glucose phosphate isomerase analysis. Bovine thymus grew during the entire 18 weeks of study. Growth of bovine lymph node was initially rapid, reaching a maximum at 2 weeks after transplantation followed by a progressive decrease in size. Transplanted bovine lymph node and thymus were morphologically similar to age-matched bovine foetal tissue for a limited time period. Fibrosis, degeneration and depletion of lymphocytes were evident 6 weeks after engraftment; changes were more severe in lymph node than in thymus whereas increases in lymphocytes, lymphopoiesis and follicle formation were evident in age-matched bovine foetal tissue. Despite growth and morphological similarities of the transplanted tissue, blood counts suggested there was no peripheralization of bovine leucocytes. Bovine immunoglobulins (IgG1 and IgG2) were detected in serum of some SCID/BG chimeric mice for a limited time. The appearance of bovine immunoglobulins at 2 weeks in SCID/BG chimeric mice depended on the age of the foetal donor (> 18 weeks) and coincided with the appearance of morphologically mature lymphocytes in the donor foetus lymph nodes. The ability to produce bovine immunoglobulins decreased 8 weeks after engraftment, coinciding with the depletion of lymphocytes in the engrafted lymph node. Lymphocyte depletion and loss of function of engrafted tissues appear the result of a lack of lymphoid progenitors normally derived from hematopoietic stem cells in the bone marrow.     

Chemically and genetically immunocompromised mice are not more susceptible than immunocompetent mice to infection with Cryptosporidium muris

The prevailing paradigm is that immunosuppressed individuals are more susceptible to infection and are at higher risk of infection from Cryptosporidium oocysts if present in drinking water. To test this hypothesis, three immune conditions were examined: genetically immunocompromised T cell deficient CD-1 nude mice, B and T cell deficient Fox Chase CB-17/IcrClB SCID mice, and chemically immunosuppressed C57Bl/6 mice. Chemical immunosuppression was induced with a single subcutaneous injection of methylprednisolone acetate (MPA) at 600 mg/kg. The MPA immunosuppressed C57Bl/6 mice were characterized by a sustained decrease in circulating CD3, CD4 and CD8 T-lymphocytes of greater than 80% and a similar decrease in B-lymphocytes. A sharp rise in circulating mature segmented neutrophils followed MPA injection, dropping sharply after 10-14 days, mirroring the decrease in lymphocytes. The cessation of oocyst production after MPA was not accompanied by a radical rise in circulating CD3 or CD4 T-lymphocytes, but rather a rise in CD8 T-lymphocytes. The ID50 for the MPA immunosuppressed C57Bl/6 mice was 122 oocysts, whereas the ID50 for the C57Bl/6 immunocompetent group was 44. The genetically immunocompromised mice showed similar differences. The ID50 for CD-1 nude mice was 166 oocysts compared to 64 in CD-1 immunocompetent mice. For Fox Chase CB-17/IcrClB SCID and the immunocompetent CB-17 mice, the ID50's were 83 and 60 oocysts, respectively. These results suggest that the lack of an immune response does not increase the ability of C. muris to establish a productive infection and produce oocysts.     

Differentiation of uterine natural killer cells in pregnant SCID (scid/scid) mice

To determine whether functional T- and B-cells can affect differentiation and/or proliferation of uterine natural killer (uNK) cells, their numbers in SCID mice (genotype, C.B.-17/Icr-scid/scid) were compared with those of control mice (genotype, C.B.-17/Icr-+/+) on days 8, 12 and 16 of pregnancy. Using biotinylated-Dolichos biflorus agglutinin (DBA) lectin staining, uNK cells can be readily classified into 4 subtypes, I to IV, from immature to mature types. The number of uNK cells was significantly lower in the decidua basalis of SCID mice than in that of control mice on day 8 of pregnancy. Particularly, the number of uNK cells of immature subtype II was significantly lower in SCID mice than in the control mice. By day 12, however, the uNK cell number in the SCID mice reached the same level as that of the control mice. It is likely that uNK cell differentiation in SCID mice was delayed during the early placentation period due to a lack of functional T and B cells.     

Periocular sarcoid in a horse

A periocular nodular sarcoid of the right upper and lower eyelids was diagnosed in an 11-year-old Thoroughbred mare. Computed tomography scan revealed the extent of the tumor. The mass was surgically debulked under general anesthesia, and the affected periocular region was injected intralesionally with Bacillus of Calmette and Guerin (BCG). An emulsion of cell wall fractions was used, which has been modified to reduce the toxic and allergic effect, but retain the antitumor activity. In total, five injections were performed at 2-week intervals. At follow-up 7 months after the last BCG injection, the tumor was completely resolved. Two years after the last treatment, the horse remains tumor-free.     

Erythrocyte-replaced mouse model for Haemoparasite studies: comparison of NOD/shi-scid and C.B-17/Jcl-scid mouse upon acceptability of human erythrocytes

The erythrocyte-exchanged chimera mouse model has become to be a significant tool for studying animal and human (hu) protozoan haemoparasites, though the usefulness of this model varies depending primarily on the acceptability of xenogeneic red blood cells (RBC). To find a superior recipient in comparison with C.B-17/Jcl mouse with severe combined immuno-deficiency (scid) mutation, we examined in this report the non-obese diabetes (NOD)/shi-scid mouse, a recently available strain of SCID. When 2.5 x 10(8) of fluorescent dye-labeled hu-RBCs were transfused, C.B-17scid mouse eliminated them logarithmically by a simple linear regression, while NOD-scid mouse eradicated hu-RBCs by a unique two-step fashion, i.e., a potent but only briefly functioning RBC eradication followed by a weak steadily functioning step. The means of regression line constance +/- their standard deviations (SD) of 205 C.B-17scid and of 213 NOD-scid mice for their short- and long-lasting steps were -0.73 +/- 0.63, -0.53 +/- 0.25 and -0.16 +/- 0.10, respectively. Hu-RBC half-lives determined from these means of C.B-17scid mice and of NOD-scid mice for the short- and long-living steps were 3.6, 4.9 and 16.3 hr, respectively. Higher hu-RBC acceptability of NOD-scid mouse, especially at their long-lasting step, was also demonstrated under at an activated state of mouse innate immunity. Treatment with 1.0 mg heat-killed Candida cells caused an acceleration of hu-RBC elimination in both mouse strains but the magnitudes for the short- and long-living steps of NOD-scid mice evaluated by "stimulation index" were only 1/2.6 and 1/7.6 of C.B-17scid mice, respectively.