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PubMed1997

Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node.

Lymphotoxin-alpha-deficient (LT-alpha-/-) mice manifest congenital absence of lymph nodes (LNs) and Peyer's patches and disturbed spleen follicle structure. The splenic white pulp areas show loss of discrete T and B lymphocyte zones, of follicular dendritic cell (FDC) clusters, and of germinal centers (GCs). Tumor necrosis factor receptor I-deficient (TNFR-I-/-) mice show similar absence of FDC clusters and GCs but retain segregation of T and B cell zones. Rarely are mesenteric LNs found in LT-alpha-/- mice. These mesenteric LNs show segregation of T and B cell zones similar to wild-type mice. In contrast, mesenteric LNs in TNFR-I-/- mice manifest grossly disturbed organization of T and B cells. Both LT-alpha-/- and TNFR-I-/- mice lacked FDC clusters in LNs and spleen. Interestingly, although both LT-alpha-/- and TNFR-I-/- mice that had been immunized with sheep red blood cells failed to form GCs in the spleen, they both developed GC-like clusters of peanut agglutinin-positive (PNA+) cells in their LNs. Furthermore, when lethally irradiated recombination activating gene (RAG)-1-deficient (RAG-1(-/-)) mice that had received spleen cells from LT-alpha-/- mice were immunized with sheep red blood cells, they failed to generate PNA+ clusters in the reconstituted spleen but showed robust PNA+ clusters in the reconstituted LNs. These data demonstrate that the signals that regulate the development of distinct T and B cell zones as well as the signals that regulate B cell activation to produce clusters of PNA+ cells differ between the spleen and LNs.

Animals↗
PubMed2002

No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria.

The phenotypes observed in mice whose uncoupling protein (Ucp2) gene had been invalidated by homologous recombination (Ucp2(-/-) mice) are consistent with an increase in mitochondrial membrane potential in macrophages and pancreatic beta cells. This could support an uncoupling (proton transport) activity of UCP2 in the inner mitochondrial membrane in vivo. We used mitochondria from lung or spleen, the two organs expressing the highest level of UCP2, to compare the proton leak of the mitochondrial inner membrane of wild-type and Ucp2(-/-) mice. No difference was observed under basal conditions. Previous reports have concluded that retinoic acid and superoxide activate proton transport by UCP2. Spleen mitochondria showed a higher sensitivity to retinoic acid than liver mitochondria, but this was not caused by UCP2. In contrast with a previous report, superoxide failed to increase the proton leak rate in kidney mitochondria, where no UCP2 expression was detected, and also in spleen mitochondria, which does not support stimulation of UCP2 uncoupling activity by superoxide. Finally, no increase in the ATP/ADP ratio was observed in spleen or lung of Ucp2(-/-) mice. Therefore, no evidence could be gathered for the uncoupling activity of the UCP2 present in spleen or lung mitochondria. Although this may be explained by difficulties with isolated mitochondria, it may also indicate that UCP2 has another physiological significance in spleen and lung.

Animals↗
PubMed1996

Changes in blood and spleen lymphocyte populations following antigen challenge in immature male chickens.

1. The effects of antigen (Ag) injection on the distribution of lymphocyte populations of Cornell K-strain male chickens were studied. 2. Two experiments were conducted. In the first, chickens were injected with Brucella abortus (BA), a purported T-independent antigen. In the second, chickens were injected with sheep red blood cells (SRBC), a T-dependent antigen. Peripheral blood lymphocytes (PBL) and spleen lymphocytes isolated at 0, 3, 6, 9, 12 and 24 h following Ag injection were stained with monoclonal antibodies (mAb) detecting B-lymphocytes, CD4+ and CD8+ cells. 3. B-lymphocytes in the blood or spleen showed no significant changes following either BA or SRBC injection. In contrast, CD4+ cells were decreased in the blood and increased in the spleen following BA and SRBC injections. CD8+ cells were decreased in both blood and spleen following BA injection but were unchanged in either blood or the spleen following SRBC injection. 4. These results indicate that there is a change in both spleen and circulating lymphocyte populations, especially T-helper cells, following Ag injection. T-helper cells are apparently the primary population involved in the initiation of humoral immunity.

Aging↗
PubMed1995

Erythrocyte-aniline interaction leads to their accumulation and iron deposition in rat spleen.

In order to understand the splenic toxicity of aniline in rats, early interaction of aniline with erythrocytes and its subsequent deposition and covalent binding to macromolecules in target (spleen) and nontarget (liver) organs have been studied. Male Sprague-Dawley (SD) rats were given 1 or 3 doses of 1 mmol/kg [14C]aniline hydrochloride (1 dose/d) by gavage and euthanized 24 h after the treatment. Among blood components, maximum radioactivity was found to be associated with red blood cells (RBCs). After 3 doses, there was 112, 79, and 67% increase in the radioactivity in the whole blood, RBCs, and hemolysate, respectively, in comparison to 1 dose. In comparison to RBCs, plasma had only 40 and 16% radioactivity after the administration of 1 and 3 doses, respectively. Spleen homogenate at 1 dose had one-third of the radioactivity in the TCA precipitate, which increased to 40% at 3 doses, while the total radioactivity increased 256% over 1 dose. Liver, which had almost double the radioactivity on a per gram tissue basis compared to the spleen at one dose, did not show any appreciable increase in the radioactivity at three doses. However, radioactivity in the TCA precipitate of liver homogenate increased by 92% after 3 doses. The iron content of the spleen in rats given 3 doses of [14C]aniline increased by 85% compared to the rats given just 1 dose. The iron content of liver did not show any change at three doses. These data thus demonstrate a dose-dependent binding and accumulation of radioactivity in erythrocytes and spleen. These interactions, along with parallel increases in the iron content of the spleen, could be critical in the splenic toxicity of anilines.

Aniline Compounds↗
PubMed1966

In vitro studies on radiation lymphoid recovery of mouse spleen.

In vitro studies, utilizing an organ culture method were reported on mutual interactions between irradiated spleen, normal bone marrow, and thymus. It has been shown; (a) that singly isolated spleen explants were incapable of lymphoid regeneration, (b) thymus had no stimulatory effect on spleen regeneration, (c) bone marrow interacted synergistically with spleen leading to appearance of lymphoid cells which were not detected in singly isolated bone marrow or spleen, and (d) no stimulation of lymphopoiesis in bone marrow was conferred by thymus in the absence of spleen. The results are discussed in terms of possible mechanisms involved in lymphoid radiation recovery in vivo.

Animals↗
PubMed1967

Hemopoietic spleen colony studies. IV. Phytohemagglutinin and hemopoietic regeneration.

The effects of phytohemagglutinin (PHA) were studied in irradiated mice to see if a definite myeloproliferative effect could be demonstrated in vivo. The data obtained suggested the following conclusions. PHA treatment of the bone marrow donor only, causes a consistent but slight reduction in transplantable spleen colony-forming unit (CFU) content of the bone marrow 24 hr after the last PHA injection, but no change was found in the proportion of the various colony types. PHA treatment of the irradiated recipient of normal bone marrow causes no change in the number of spleen colonies. However, 8-day colonies are only about half normal size, are much more likely to be of mixed cell types, contain many large undifferentiated blastoid cells, but fewer transplantable CFU. The spleen sinusoids are packed with hemopoietic cells. Spleen colonies developing in hosts receiving daily injections of PHA show, in addition to the usual spectrum of cell types, a high proportion of unusual blastoid cells resembling the PHA transformed peripheral lymphocytes seen in vitro. The function of these cells is not known, but they may represent augmented proliferation and/or transformation of stem cells. PHA administered after irradiation significantly increased the number of endogenous spleen colonies, and, at certain doses of irradiation, improved postirradiation survival. PHA administered before irradiation had no effect on the number of endogenous spleen colonies formed, or on postirradiation survival. On the basis of these and other data, possible modes of action of PHA are discussed.

Animals↗
PubMed1969

Immunocompetence of spleen cells from neonatally thymectomized mice conferred in vitro by a syngeneic thymus extract.

Impaired immunological competence of spleen cells from neonatally thymectomized C57B1/6 young adult mice was apparent when these cells were tested in an in vitro graft-versus-host assay. Spleen cell inocula prepared from thymectomized mice did not induce enlargement of (C3H/eb x C57BI/6)F(1) newborn spleen explants, whereas the same number of cells from intact donors consistently initiated splenomegaly. Spleen enlargement was observed, however, when the explants were challenged by cells from thymectomized donors in the presence of syngeneic thymus extract, indicating that the spleen cells in suspension attained immunological competence under the influence of a non-cellular component of the thymus. Immunocompetence was also evident when the cells from thymectomized donors were first incubated with thymus extract for 1 hr and subsequently tested for reactivity. Cells from the same thymectomized donor mice exposed in parallel to extracts from syngeneic spleen or mesenteric lymph node at an equivalent protein concentration did not initiate a graft-versus-host response. These experiments demonstrate that immune reactivity in the graft-versus-host response involves activation of lymphoid cells by a humoral factor of the thymus acting directly upon these cells.

Aging↗
PubMed1971

Leukemia evoked with 7,8,12-trimethylbenz(a)anthracene in rat. I. Changes in spleen and thymus.

An early sign of erythroblastic leukemia in rat was nodule formation in the spleen. Hyperplastic foci of stem cells, indistinguishable histologically from leukemic stem cells, were found in the red pulp whereas the malpighian corpuscles were uninvolved. Anemia is a normal phenomenon in immature rats and the spleen of the prepubertal rat possesses considerable hemopoietic potential. Pulse-doses of 7, 8, 12-trimethylbenz(a)anthracene prevented the physiologic hematological development of maturing rats and was associated with subsequent development of leukemic stem cells in the red pulp of the spleen. Significant enzyme changes were observed in leukemic spleens. Compared with the spleens of normal littermates, the concentration of lactate dehydrogenase rose while that of malate dehydrogenase fell; the content of alkaline phosphatase rose whereas acid phosphatase fell. Increased alkaline phosphatase activity in leukemic spleen was attributed to nonleukemic foci of myelopoiesis.

Adrenal Glands↗
PubMed1974

Cell-mediated immune responses in vitro. I. Suppression of the generation of cytotoxic lymphocytes by concanavalin A and concanavalin A-activated spleen cells.

The effects of soluble concanavalin A (Con A) or Con A-activated spleen cells on the generation of cytotoxic lymphocytes (CL) in mixed leukocyte cultures (MLC) were examined. Mitogenic concentrations of soluble Con A or small numbers of Con A-activated spleen cells substantially inhibited CL responses. The suppression was partial rather than absolute and was critically dependent upon the concentration and time of addition of soluble Con A or Con A-activated spleen cells to the MLC. Suppressive effects of Con-A activated spleen cells were mediated by T cells since suppressor cell activity was abrogated by treatment of spleen cells with anti-theta serum and complement before or after Con A activation. X irradiation of spleen cells before Con A treatment also abrogated generation of suppressor cell activity. After activation by Con A, however, the function of suppressor cells was radioresistant. Although the precise mechanism(s) of suppression is, as yet, unknown, the precursors of CL must be exposed to Con A-activated cells during the early phases of the immune response for suppression to occur. Kinetic studies revealed that suppression of CL responses was not due to a failure to initiate an immune response, but represented a response which developed initially, but subsequently aborted. The relevance of these observations to the concepts of T-cell-T-cell interaction and regulatory control of immune responses by T cells is discussed.

Animals↗
PubMed1979

Friend erythroleukemia antigen. A viral antigen specified by spleen focus-forming virus and differentiation antigen controlled by the Fv-2 locus.

Serum from C57BL/6 (B6) mice hyperimmunized with NB-tropic Friend virus complex (FV) was cytotoxic for FV-induced erythroleukemic spleen cells and B6 Friend-murine leukemia virus (F-MuLV) lymphoma cells. Cytotoxic activity for erythroleukemia cells remained after repeated absorption of B6 anti-FV antiserum with Friend-Moloney-Rauscher MuLV lymphoma cells but was removed by absorption with erythroleukemia cells induced by FV or Rauscher Vrus. This serologic test system identified a previously unrecognized cell-surface antigen of mouse leukemia, designated Friend Erythroleukemia (FE) antigen to signify its appearance as a determinant of virally induced erythroleukemic differentiation. FE antigen was not detected on 15 transplanted or primary hematopoietic neoplasms, nor was it detected on cells infected with ecotropic, xenotropic, or dualtropic MuLV isolates in tissue culture. Two spleen focus-forming virus (SFFV) nonproducer cells of rats and one of mice express FE antigen in amounts comparable to primary erythroleukemia cells. Absorption tests with FE typing serum indicated that FE antigen was expressed on bone marrow and spleen but not thymus, lymph node, or peripheral blood of uninfected AKR, BALB/c, DBA, and SWR mice; all five tissues from B6 and C57L were negative. Quantitiative absorption tests indicated that the expression of FE antigen, though much lower than on erythroleukemic cells, was greatest on fetal liver, less on bone marrow, and lowest on spleen from BALB and SWR mice. Treatment of BALB/c or SWR fetal liver, bone marrow, spleen, thymus, or lymph node cells with FE typing serum did not result in significant lysis. These observations are consistent with the interpretation that FE antigen is expressed by a minor cell population present in fetal liver, bone marrow, and spleen. Expression of FE antigen, determined by absorption with bone marrow cells, cosegregated with inheritance of the Fv-2s allele in the 17 inbred, 7 recombinant inbred, and 4 congenic mouse strains tested. In summary, the FE antigenic system identifies a cell-surface determinant that has the properties of a SFFV-specified antigen and hematopoietic differentiation alloantigen controlled by the Fv-2 locus. The similarity of FE antigen to Abelson antigen may provide insight into the pathogenic properties of defective transforming MuLV.

Animals↗
PubMed1980

Antigen- and receptor-driven regulatory mechanisms. V. The failure of idiotype-coupled spleen cells to induce unresponsiveness in animals lacking the appropriate VH genes is caused by the lack of idiotype-matched targets.

A/J anti-p-azobenzenearsonate (ABA) antibodies bearing cross-reactive idiotypic (CRI) determinants, when coupled to spleen cells and then injected intravenously into naive animals, stimulate suppressor T cell (Ts) responses. Moreover, previous studies have demonstrated that the ability of such idiotype-coupled spleen cells to induce immune unresponsiveness to subsequent immunization with ABA-coupled spleen cells is linked to Igh-1 genes. Thus, CRI bearing antibodies from A/J mice, when conjugated to normal BALB/c spleen cells in vitro and then injected intravenously to syngeneic BALB/c mice, failed to induce tolerance in these animals. However, spleen cells taken from these animals transferred significant degrees of suppression to Igh-1 congenic C.AL-20 but not to H-2 congenic, Igh-1 distinct B10.D2 mice. Therefore, the failure of CRI-coupled spleen cells to induce suppressor cell- mediated unresponsiveness in animals unable to express the appropriate VH genes (i.e. BALB/c and B10.D2) appears to be caused by the lack of idiotype- matched targets. The notion that the ability to express certain Vn genes in the recipient animal is a prerequisite for suppressor cell function was further supported by the observation that suppressor cells induced in C.AL-20 mice failed to transfer any degree of suppression to BALB/c mice. The ability to transfer suppression from BALB/c mice to C.AL-20 mice is a T cell- dependent phenomenon, since in vitro treatment with anti-Thy 1.2 antiserum and complement completely abrogated suppressor cell function. Furthermore, these suppressor T cells are antigen specific and can be enriched on idiotype-coated petri dishes, indicating they possess anti-idiotypic receptors. Therefore, appropriate anti-idiotype and idiotype interaction is essential for the manifestation of suppressor T cell function in ABA-specific suppressor pathways.

Animals↗
PubMed1986

Macrophage plasma membrane and secretory properties in murine malaria. Effects of Plasmodium yoelii blood-stage infection on macrophages in liver, spleen, and blood.

We have studied the effect of infection with the blood-stage of Plasmodium yoelii 17X, a nonlethal parasite, on plasma membrane antigens, receptors, and secretory properties of macrophages (M phi) in murine liver, spleen, and blood. mAb F4/80 (M phi specific), F7/4 (a marker for immature and immunologically activated M phi, as well as neutrophils), and Mac-1, which binds to the type 3 complement receptor, were used to measure the distribution and total content of antigens in situ and to assay surface expression of antigens on M phi isolated by collagenase perfusion-digestion and adherence. We also examined respiratory burst activity after stimulation with PMA, FcR activity, Ia antigen expression, and binding of 125I-mannose-BSA and unopsonized sheep erythrocytes by isolated M phi. In the normal animal, spleen M phi expressed Mac-1 and F7/4 antigens and relatively high levels of respiratory burst activity, in contrast to Kupffer cells in liver, where all three features were virtually absent. The introduction of parasitized erythrocytes into the circulation resulted in a large influx of F4/80+ M phi into the blood, liver, and spleen, where local M phi proliferation could also contribute. Liver M phi during malaria infection showed increased Mac-1 and 7/4 antigen and an increased respiratory burst potential compared with uninfected controls. Increases in total, but not specific activity of FcR, Ia antigen, and binding of unopsonized sheep erythrocytes were found in spleen and liver M phi populations after infection. In both populations, there was an early but persistent marked reduction in specific binding and uptake of 125I-mannose-BSA. These results confirm and extend observations that normal Kupffer cells are relatively homogeneous in morphology, surface markers, and anatomical location, in contrast to M phi in normal spleen, and that both of these populations differ from resident M phi elsewhere, including the peritoneal cavity. In the course of infection by P. yoelii, M phi with high levels of opsonic receptors (CR3, FcR) and respiratory burst potential are mobilized in large numbers at specific sites such as liver and spleen, in accordance with an important role for M phi in the clearance of parasitized erythrocytes from blood.

Animals↗
PubMed1988

Properties of isolated red pulp macrophages from mouse spleen.

Dense monolayers of large, adherent macrophages were prepared from the red pulp of mouse spleen. These sinus-lining phagocytes resembled liver Kupffer cells in morphology, as well as expression of F4/80 and class II MHC antigens and receptors for IgG. C3-coated red cells attached at low levels to spleen macrophages, but attachment and endocytosis were enhanced on fibronectin-coated surfaces. The ionophore A23187 induced spleen macrophages to synthesize prostaglandin E2, but like Kupffer cells, spleen macrophages did not synthesize leukotrienes and made relatively small amounts of HETE and 12-hydroxyheptadecanoic acid. Resident spleen macrophages did not produce H2O2, but splenic inflammatory cells, induced by infection of animals with Listeria monocytogenes, actively released H2O2. We conclude that the functional properties of resident, sinusoidal-lining macrophages in liver and spleen are similar to one another but distinct from other pools of phagocytes.

Animals↗
PubMed2002

B-1a B cells that link the innate and adaptive immune responses are lacking in the absence of the spleen.

Splenectomized individuals are prone to overwhelming infections with encapsulated bacteria and splenectomy of mice increases susceptibility to streptococcal infections, yet the exact mechanism by which the spleen protects against such infections is unknown. Using congenitally asplenic mice as a model, we show that the spleen is essential for the generation of B-1a cells, a B cell population that cooperates with the innate immune system to control early bacterial and viral growth. Splenectomy of wild-type mice further demonstrated that the spleen is also important for the survival of B-1a cells. Transfer experiments demonstrate that lack of these cells, as opposed to the absence of the spleen per se, is associated with an inability to mount a rapid immune response against streptococcal polysaccharides. Thus, absence of the spleen and the associated increased susceptibility to streptococcal infections is correlated with lack of B-1a B cells. These findings reveal a hitherto unknown role of the spleen in generating and maintaining the B-1a B cell pool.

Animals↗
PubMed1984

Induction of interferon gamma in mouse spleen cells by culture supernatants of mycoplasma arthritidis.

Factor(s) in the supernatant of cultured mycoplasma arthritidis (MAS) represented potent inducers of interferon (IFN) in cultures of mouse spleen cells. Responding mouse strains included A/J, BALB/c, CBA, C3H, and DBA/2 whereas spleen cells of C57BL/6 and C57BL/10 mice were nonresponders. Interferon production was controlled by the I region of the H-2 locus. Treatment of CBA spleen cells by anti-thy-1 antibody plus C abolished IFN production. A similar effect was seen when CBA spleen cells were freed of macrophages by passage through Sephadex G-10 columns. Pure macrophages themselves, however, were not producing IFN when treated by MAS. Macrophage-depleted CBA spleen cells could be reconstituted to produce IFN by the addition of 2-ME. Interferon induction by CBA spleen cells was independent of lymphoproliferation as evidenced by experiments utilizing mitomycin C. The IFN induced by MAS represented IFN gamma (gamma), since it was acid-labile and neutralized by a specific antiserum.

Animals↗
PubMed2005

Laparoscopic splenopexy of a pediatric wandering spleen by creation of a retroperitoneal pocket.

Wandering spleen is a rare condition in which the spleen is attached by a long, vascular pedicle and lacks its usual peritoneal attachments and supporting ligaments. This condition predisposes the spleen to torsion and infarction. We report the case of a 2-year-old boy with a history of intermittent abdominal pain and early satiety who presented with abdominal pain and severe gastric distention. A work-up including computed tomographic and ultrasonographic imaging suggested a wandering spleen. The diagnosis was confirmed during laparoscopy, and splenopexy was performed by anchoring the spleen in a retroperitoneal pocket in the left upper quadrant at the level of the tenth rib. To our knowledge, this is the first reported case of minimally invasive splenopexy for wandering spleen that involves the creation of a retroperitoneal pocket without the use of mesh. The authors believe that this is a safe and effective method that takes advantage of laparoscopy and avoids the risk of infection and complications associated with the use of synthetic material.

Abdominal Pain↗
PubMed2006

Auxiliary liver organ formation by implantation of spleen-encapsulated hepatocytes.

Hepatocyte transplantation is an attractive alternative to orthotopic liver transplantation. However, its application has been limited because of its short-term success only. Here we report a new approach to hepatocyte transplantation resulting in the generation of an auxiliary liver in vivo. Isolated primary hepatocytes were encapsulated in isolated spleens and then transplanted by attaching the spleens to the livers of recipient animals (mice or rats) using biodegradable adhesive. A vascular network was rapidly established, and protein molecules circulated freely between the transplanted spleen and the liver, to which they adhered. In contrast, the spleen, which did not adhere to the liver or adhered elsewhere (adipose tissue or peritoneum), did not become vascularized but shrank and died. Encapsulation of hepatocytes in an isolated spleen enhanced their survival significantly, and co-encapsulation of Engelbreth- Holm-Swarm gel together with the hepatocytes further enhanced it. The encapsulated hepatocytes expressed liver-specific differentiation genes for more than 3 weeks. Plasma albumin concentrations in Nagase analbuminemic rats began to increase 3 days after transplantation. The transplanted hepatic cells migrated into the liver parenchyma, whereas the spleen was absorbed. Thus, we have developed a novel, simple approach for the rapid and efficient formation of functional auxiliary liver using a modified hepatocyte transplantation method.

Animals↗
PubMed1996

Induction of hprt gene mutations in splenic T-lymphocytes from the rat exposed in vivo to DNA methylating agents is correlated with formation of O6-methylguanine in bone marrow and not in the spleen.

The suitability of splenic T-lymphocytes as a substitute tissue for detection of genotoxic effects induced in vivo by chemical agents that are organ-specifically activated was tested in rats exposed to single doses at the potent lung-carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acetoxymethylmethylnitrosamine (AMMN) or N-methyl-N-nitrosourea (MNU). NNK, AMMN and MNU methylate DNA most likely via the formation of a methanediazohydroxide ion that decomposes to a methyl diazonium ion. For all three agents, an increase in the levels of 06-methylguanine and 7-methylguanine in DNA of rat liver and lung was detected by reverse phase HPLC and electrochemical detection. Treatment with NNK did not result in the formation of O6-methylguanine and 7-methylguanine in DNA of bone marrow and spleen, corresponding with the absence of metabolic activation pathways for this compound in these tissues. For AMMN formation of both 06-methylguanine and 7-methylguanine was detectable in DNA of the spleen, whereas in DNA of bone marrow only very low frequencies of 7-methylguanine were found at a toxic dose. MNU induced O6-methylguanine and 7-methylguanine in both spleen and bone marrow. Using splenic T-lymphocytes from the rat no increase above control levels of the hprt mutant frequencies was found for NNK and AMMN for all exposure levels tested, 32 days after chemical exposure. For MNU a dose-dependent increase in hprt mutant frequency was found at exposure levels of 0.097 mmol/kg up to 0.582 mmol/kg. DNA sequence analysis was performed on PCR products of hprt cDNA from 39 MNU-induced 6-thioguanine-resistant T-lymphocyte clones. Single base pair substitutions were found in 25 of these mutants (64%), GC-->AT transitions being the predominant type of mutation (19 of 25; 76%). These mutations are probably caused by mispairing of 06-methylguanine with thymine during DNA replication. The results indicate that formation of mutagenic lesions in the spleen is not correlated with an enhanced frequency of 6-thioguanine-resistant splenic T-lymphocyte clones from rats, 32 days after exposure in vivo to DNA damaging agents. This suggests that mutation-fixation in T-lymphocytes does not occur in the spleen but at other sites in the body such as bone marrow, after which these mutated cells migrate to the spleen.

Alkylating Agents↗