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PubMed1977

Intrahepatic transplantation of pancreatic islets in the rat.

Islets of Langerhans from isogeneic donor rats were transplanted directly into the hepatic parenchyma of recipients which had been made severely diabetic by streptozotocin (glycaemia ranging between 400 and 1090 mg%). Complete control lasting up to 13 months was achieved in 65% of recipients by using 600-800 islets. Following intravenous glucose administration, each rat responded similarly to normal rats with a rapid but reduced release of insulin. Cytoimmunofluorescence and electron microscopic studies demonstrated the presence of both functional insulin and glucagon cells, within the transplanted islets. It is suggested that for various reasons direct intrahepatic transplantation might become the preferred method for islets.

Animals↗
PubMed1977

Effects of cyclophosphamide and of busulfan on spleen colony-forming units and on hematopoietic stroma.

The effects of cyclophosphamide (CY) and busulfan (BU) on the hematopoietic stromal function (HS-P) of mouse marrow were evaluated. Stromal function of femoral marrow was assessed by implanting the test femur s.c. into an isogeneic host and determining the number of CFU-S in the implant 6 weeks later. Since the CFU-S have been shown previously to be primarily of host origin, this presumably measures the abilit- of donor hematopoietic sites to harbor host CFU-S. After injection of CY, the number of CFU-S in the marrow fell but recovered to normal within 6 weeks. The HS-P function fell to half-normal after 10 mg of CY and did not regenerate detectably in 6 weeks. On the other hand, 2 mg of BU i.p. caused a lesser initial decline in the number of CFU-S, but recovery was still incomplete after 6 weeks. BU given p.o. had a more marked effect on CFU-S and caused a significant decline in the HS-P function. Doses of CY (5 mg/dose) given intermittently appear to cause cumulative damage to HS-P function. HS-P function did not, in any experiment, recover significantly in the 6 weeks following the last dose of CY. This result suggests that large doses of the alkylating agent CY causes prolonged and perhaps permanent HS-P damage. This damage to the HS-P is cumulative when the CY is given at weekly intervals. Despite lack of HS-P recovery, CFU-S regenerate rapidly after CY therapy is stopped. On the other hand, BU also causes damage to the HS-P. However, even when BU is given at a dosage that does not significantly affect the HS-P, CFU-S recovery is delayed, suggesting that BU affects the CFU-S in a manner that differs qualitatively from that of CY.

Animals↗
PubMed1977

Effect of dose, route, and schedule of BCG on antibody titer and survival of murine skin grafts across a weak histocompatibility barrier.

Skin was transplanted from male to female C57BL/6JRC mice. Bacillus Calmette-Guérin (BCG) was administered once subcutaneously, intramuscularly, or intraperitoneally either 14 days prior to grafting or on the day of grafting in a dose of 5 X 10(5), 5 X 10(6), or 5 X 10(7) microorganisms. Serum antibody to BCG was assayed using complement fixation. There was a linear inverse relation between skin graft rejection and dose of BCG (p less than .01) such that the lowest dose of BCG was the most effective. The IM and SQ routes were more effective than the IP route. Schedule did not have significant effect on skin graft survival. Time to appearance of antibody correlated directly with dose. The prolonged survival of skin grafts combined with early appearance of antibody to BCG suggested that high doses of BCG could result in antigenic competition.

Animals↗
PubMed1977

Growth of human tumors in lethally irradiated mice reconstituted with syngeneic fetal liver cells.

Transplantation into lethally irradiated mice of hematopoietic and lymphoid cells from immature donors which hypothetically will not mount a cell mediated attack against simultaneously inoculated human tumor cells has resulted in tumor engraftment and growth in long-term surviving radiation chimeras. Twenty-four hours after lethal irradiation, A or CBA mice were given iv injections of 2 X 10(7) fetal liver cells from syngeneic donors of 14, 16, or 18 days of embryonation and sc injections of 1, 3, or 6 X 10(6) human choriocarcinoma (C-1, C-2, and C-3) cells or human breast carcinoma (B-1) cells that had been maintained in culture. Palpable tumors greater than or equal to 5 mm were noted in 18/22 mice injected with C-1, 9/16 with C-2, 10/10 with C-3, and 18/30 with B-1. Tumors of 17 (31%) of mice remained palpable until death of the animal or until termination of the experiment 100 days post inoculation. Histologic study of autopsy specimens revealed malignant tumors with occasional pulmonary metastases. Human chorionic gonadotropin was found in the serum of mice that received choriocarcinoma cells.

Animals↗
PubMed1978

Effects of ultraviolet light on nude mice: cutaneous carcinogenesis and possible leukemogenesis.

Squamous cell carcinomas were induced by ultraviolet irradiation in the skin of all T-cell deficient nude mice rendered sufficiently long-lived by reconstitution with syngeneic splenic or thymic cells. All homozygous hairless mice similarly exposed developed squamous cell carcinomas. Striking granulocytic proliferation was provoked in one hairless and in five reconstituted nude mice; two of the latter were interpreted as having true granulocytic leukemia.

Animals↗
PubMed1978

Marrow transplantation for acute leukemia.

Marrow transplantation enables the physician to ignore the complications of marrow toxicity which limit the chemotherapy of leukemia and makes it possible to explore new drugs and regimens. The results of marrow transplantation for 154 cases of end-stage acute leukemia carried out by the Seattle Marrow Transplant Team are summarized. Even with the use of an HLA matched sibling as a donor, allogeneic marrow transplantation is followed by graft-versus-host disease in about 2/3 of the patients which is of life-threatening severity in approximately 20%. An actuarial plot of the recurrence rate of leukemia following transplantation shows that about 2/3 of the recipients of either allogeneic or syngeneic (identical twin) marrow will relapse within 2 years. However, about 1/3 will not relapse and recurrence of leukemia has not been observed after 2 years. A Kaplan-Meier plot of the survival of 29 syngeneic marrow recipients and 110 recipients of allogeneic marrow shows an almost flat survival curve in the period f om 2 to 7 years after transplantation. The leukemia free survival of these patients on no maintenance chemotherapy constitutes an operational definition of cure in these patients.

Bone Marrow↗
PubMed1978

Maternal immunological recognition mechanisms during pregnancy.

One of the most intriguing shortcomings of modern immunology, especially transplantation immunology, is its failure to provide a satisfactory final explanation for the consistent non-rejection of immunogenetically alien conceptuses in utero, even in specifically preimmunized females. Certainly, there is no shortage of hypotheses. Over the past few years various observations have utterly refuted the simplistic notion that the much-mated but nulliparous or gravid females are immunologically unaware of the presence and activities of allogeneic cells transiently or chronically within their reproductive tracts. This evidence has engendered the belief that some kind(s) of active response(s) on the part of the female, following early recognitive events, plays an important, if not essential, role, in conjunction with adaptive hypoantigenicity of the trophoblast, not only in conferring selective benefits upon the conceptus from the time of implantation, but also in affording it protection from the possible hazards of a cellular immunity. Evidence is emerging that during mating, implantation, placentation, and gestation (1) various fetal and histocompabibility antigens are presented to the mother in a unique manner; (2) she does respond to these; and (3) her responses aid in the establishment and maintenance of a harmonious state of immunological coexistence with her fetus. There are reasonable grounds for believing that a complete understanding of the immunobiology of the maternal-fetal relationship may facilitate significant advances in both transplantation and tumour immunology.

Animals↗
PubMed1976

Effect of antiserum on transplantable hematopoietic colony-forming units during Rauscher leukemia development.

Studies have been carried out to determine the sensitivity of hematopoietic CFU-S from Rauscher leukemic mice to an antiserum against the disease prepared in syngeneic mice. Test of this antiserum against Rauscher virus prior to injection showed it to be effective both in vitro and in vivo. At the same time, normal serum was shown to be without effect either against the CFU-S or against the virus. Spleen CFU-S were obtained from control and leukemic mice over a sequence of days following Rauscher virus injection and assayed by transplantation technique. Prior to transplantation these were incubated in vitro in either normal syngeneic serum or syngeneic antiserum. Incubation with antiserum had no effect on CFU-S obtained from the spleens of normal mice. However, incubation in this antiserum of spleen CFU-S from Rauscher leukemic mice resulted in a reduction of up to 50% in their colony-forming ability. Additional tests with guinea pig complement suggested that the levels of inactivation seen are not complement limited. This antiserum-induced reduction in colony formation was first evident in the second week after the injection of virus, coincident with the onset of splenomegaly in the leukemic mice. Thereafter, sensitivity of CFU-S to the antiserlm could be detected up to the terminal point of the leukemia (44 days).

Animals↗
PubMed1977

Cell surface components of carcinogen-induced lymphoid tumors in SJL/J mice.

Preleukemic cells could be detected in the bone marrow cell population of SJL/J mice within several days after induction of leukemia by repeated feedings with a chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Bone marrow cells collected 7, 30 or 60 days following carcinogenic treatment, developed lymphoid tumors upon transplantation into syngeneic irradiated recipients. The incidence of these tumors varied between 40--45% when the bone marrow cells were collected and transferred 7--30 days after feeding with DMBA, and raised to an incidence of 80% when transferred 60 days after carcinogen administration (compared to 50% incidence in the DMBA-treated bone marrow donors). A survey of several cell surface components on the lymphoid tumor cells, obtained after transplantation of preleukemic cells, indicated that most of the tumor lines bore both the Thy-1.2 antigen (weak) and the Fc receptor, whereas the rest were positive only for the Fc receptor. None of these tumor cell lines would yield a significant amount of cell-bound immunoglobulin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Restoration by serum thymic factor of colony-forming unit (CFU-S) entry into DNA synthesis in thymectomized mice after T-dependent antigen treatment.

Adult thymectomy prevents stimulation of hematopoietic stem cells as measured by colony-forming units (CFU-S) if T-dependent antigens are injected, but not when T-independent antigens are used. This can be observed as soon as 10 to 15 days after thymectomy. The serum thymic factor can restore CFU-S response to T-dependent antigens in thymectomized mice.

Animals↗
PubMed1975

Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity.

Lymphoid cells from many normal mice of a variety of inbred strains were found to have reactivity, in a 51Cr release cytotoxicity assay, against several syngeneic and allogeneic tumors. Very high reactivity was seen with effector cells from athymic nude mice, which was consistent with other evidence that the reactivity was not T-cell dependent. Target cells susceptible to lysis included tumors induced by oncogenic type-C viruses but also tumors induced by other means and expressing endogenous type-C viruses. The levels of natural reactivity were influenced by age, with highest cytotoxicity produced by cells from 5- to 8-week-old mice. Lymph-node cells, spleen cells, peritoneal exudate cells and peripheral blood lymphocytes all had cytotoxic reactivity. The specificity of the reactions was analyzed in detail by ana inhibition assay. Evidence was obtained for natural reactivty against several different antigens, each apparently associated with expression of murine endogenous type-C viruses.

Age Factors↗
PubMed1975

Restoration of specific immunity against SV40 tumor-specific transplantation antigen to lymphoid cells from tumor-bearing mice.

Specific cell-mediated immunity to SV40 tumor-specific transplantation antigen (TSTA) in BALB/c mice undergoing progressive tumorigenesis by syngeneic SV40-transformed cells (VLM) was investigated in vivo using a tumor-cell neutralization test. Specific cellular reactivity to SV40 TSTA was not detected in BALB/c mice bearing large tumors (10-15 mm mean diameter) but was demonstrable after tumor excision. Specific cytotoxic reactivity against syngeneic SV40-transformed cells in vivo could be restored to lymphoid cells from VLM tumor-bearing mice either by culturing the lymphoid cells in vitro or by treating them with papain or trypsin. Enzyme-treated lymphoid cells from MCA tumor-bearing BALB/c mice had no cytotoxic reactivity against VLM cells. These studies suggest that tumor-bearing hosts possess lymphocytes which are sensitized to the TSTA of the tumor but that the reactivity of these lymphocytes is blocked.

Animals↗
PubMed1975

Spleen-cell reactivity against transplanted neurogenic rat tumors induced by ethylnitrosourea: uncovering of tumor specificity after removal of complement-receptor-bearing lymphocytes.

Spleen cells from BDIX-rats bearing either GVlAl-tumor (a syngeneic mixed glioma) or NVlAc-tumor (a cloned syngeneic neurinoma of the peripheral nervous system) were cytotoxic to both tumor cells in vitro. However, the tumors displayed individually distinct antigenic specificities by in vivo rejection tests. Their in vitro cross-reactivity disappeared when a particular subpopulation of the spleen cells was used. The procedure of lymphocyte purification included three consecutive steps: treatment with carbonyl iron and magnetism, passage through a nylon wool column, and finally removal of complement receptor-bearing cells present in the colum-excluded population. Cross-reactivity between the syngeneic tumors persisted after the first two steps of lymphocyte purification. In contrast, specific cytotoxic reactions were observed against each individual tumor subsequent to the removal of the remaining C3 receptor-positive but surface Ig-negative cells. While killer cells were present in normal spleen-cell populations, these were almost completely eliminated by passage through the nylon wool column.

Animals↗
PubMed1975

Transformation of mouse cells after infection with ultraviolet irradiation-inactivated herpes simplex virus type 2.

A transformed mouse cell line (H238) was obtained following the infection of 238 mouse cells with ultraviolet (UV) irradiation-inactivated herpes simplex virus type 2 (HSV-2). The transformed cells produced tumors with a 100% incidence within 8 weeks in 6-week-old syngeneic BALB/c mice at an inoculum of 1 times 10(6). Indirect immunofluorescence (IF) tests revealed the presence of HSV antigens in the transformed cells. Antibodies to HSV-2 were found in the sera of tumor-bearing animals by neutralization and IF techniques. Neither HSV-2 infectious virus nor viral antigens could be detected by the transfer of transformed-cell DNA into permissive cells.

Animals↗
PubMed1975

Cell-mediated cytotoxicity to chemically-induced rat tumours.

Cell-mediated immune reactions against carcinogen-induced rat tumours were demonstrated by the in vitro microcytotoxicity test. Lymph-node cells from syngeneic rats immunized against individual aminoazo-dye-induced hepatomas or 3-methylcholanthrene-induced sarcomas were cytotoxic for cells of the immunizing tumour compared with the effects of normal lymph-node cells. Only a low level of cross-reactivity was detectable against target cells derived from otherr tumours. Conversely, lymph-node cells from tumour -bearing rats were cross-reactive against a range of tumour cells, suggesting that the tumour-bearer was sensitized against a common antigen(s) as well as the individually specific antigen associated with these tumours. Lymph-node cells were reactive at an early time (from day 2) after tumour implantation and their cytotoxic potential persisted until terminal stages of tumour growth. Spleen cells from tumour-bearer and tumour-immune donors also exhibited comparable cytotoxic reactivities of the same specificity as that shown by lymph-node cell preparations. These findings are discussed in relation to the development of cell-mediated immune responses in the tumour-bearing rat and in immunized rats which are capable of rejecting transplanted tumour cells.

Animals↗
PubMed1975

Alien histocompatibility determinants on the cell surface of sarcomas induced by methylcholanthrene. I. In vivo studies.

Groups of BALB/c mice were immunized to normal tissues (skin and/or liver plus kidney) of C3Hf, C57Bl/6, DBA/2 and AKR strains and challenged with either of two syngeneic 3-methylcholanthrene-induced immunogenic sarcomas, ST2 and TZ15, or with a "spontaneous" non-immunogenic BALB/c sarcoma, B2. It was found that anti-C3Hf and anti-DBA/2 immune mice were significantly protected against the growth of ST2, whereas anti-AKR immune mice rejected TZ15; no protection was elicited by immunizing with normal tissues of any strain against B2, which lacked individual tumor-associated transplantation antigens (TATA). The reciprocal experiment, i.e. the immunization of BALB/c mice with tumor cells and challenge with skin grafts of different strains, was also carried out with ST2 and TZ15. Accelerated rejection of all the various allogeneic skins was observed in anti-ST2 immune mice and of AKR and C3Hf skin in anti-TZ15 immune animals. In addition the Winn test demonstrated that lymph-node cells of BALB/c mice immune to C3Hf or DBA/2 tissues were specifically inhibitory for ST2, and that lymph-node cells immune to AKR tissues protected against TZ15. In a further experiment both ST2 and TZ15 tumors were left to grow in (C3Hf X BALB/c)F1, (C57Bl/6 X BALB/c)F1, (BALB/c X DBA/2)F1 and (BALB/c X AKR)F1 mice; the tumors were then excised and the "immune" mice challenged with the related tumor to measure their immune response in comparison with that elicited by the same procedure in BALB/c mice. ST2 was highly immunogenic in syngeneic BALB/c mice and in all the hybrid combinations except (C3Hf X BALB/c)F1 mice, where it completely lost its immunogenicity; TZ15 showed a certain loss of immunogenic strength in (BALB/c X AKR)F1 hybrids. It was concluded that TATA of ST2 contain antigenic determinants expressed on the normal cells of C3Hf and DBA/2 strains, and that TATA of TZ15 are likely to share antigens with AKR normal tissues.

Animals↗