Studies on chemically induced rat tumors. II. Partial protection against syngeneic lethal tumors by cloned syngeneic cytotoxic T lymphocytes (original) (raw)
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Cytotoxic T Cell Responses to a Syngeneic Tumour: Conditions for Primary Activation in Vitro
Australian Journal of Experimental Biology and Medical Science, 1978
Primary cytotoxic responses of lJliA/2 iynipli nuilc ct-lls to a synfifiit'if tumour (the iniistnt-ytoma P815) lia\f been Kfnc-ratcd in vitro. Tindevelopment of tlH'si' ri-spiiiLses is tlfpfiiilcnt on the attilitioii of a MiliiMifactor (CSCS) whit-h h prcniuc-etl hy ttniraiiavalm A-aiti\aIe<l spleen cflK. The ri-^ponse is iiiefljutitl hy T lymphticytcs. tan be ilctttttKi at low efltttor to tiirRct cell ratios and is directed aRninst PSI5 tumour-a.sstKiated antigens. INTROIHJCTIOX. In vitro T cell acti\ati()n rt<niirfs antigen pre?>eiitation to ihi-rcsimrasive cell in combination with an intliittive stinntlus provided by the stiniulatr»r tell, or acccssor>-celts in the culture (Lullrrty. .Misko ami (;(M)lcy. 1974; Lalft-rty antl Cunniiiiiliiim. 1975; Bach Bjuh and Sondfl, 1970; Davidson. H)77). In tlic al)st.-iici' of ihi.s induttivc signal, which is pro\ idcil by mctalmliialK active cells of the l>iiiphi)c>tf-niiKidphane class, aiiiijiiMi will not initiate T cell activation (TalmaKe et al. 1977). The siiptTiiatant nicdiimi from concanavalin .A-activated spleen cells (CSCS) pnniiles a source of this costimulator requirwl for c>toto.\ic T cell activation (Taliiiajie et al.. U)77). Primary cytotoxic rt^ptmses of DBA 2 KmphiK'ytes to tbe s>nKeneic tumour, the DBA/2 mastot'j tomti P813. have bt-cn deinmwtratfd (Takei. Levy and Kilbum, 197fi; I.undak and Raiclt. 1973). The-Sf rt'spon.scs arc specific but weak, requiring hiKh cllector In target cell ratios (iM-twecn IOO and IO(H):I) and long incubation periods Intwern effector antl target cells to ilemoiLstratc activit\. In (his report we SIK)W that cytiitoxic T cell resi>onses to s\Tigeneic hmiour associated ai)tigeii% un P8I5 can be greatly enhanced by addititin of CSCS to tbe in vitro culture s>'stem. MATERIALS AXD MKTHODS. Prfj>aration of eoncanavaliu .\-actiV4ited st'leen eeli .supernatant (CSCS) CSCS was initially prepantl as descrilxxl previously (Lalferty and \V(x)Inoujih. 1977) bul was later prepared usiiifi a iniKlification of a method descrilx-d by Pick and Kntkcs (IS)77); CBA (H-2'') spleen cells (10 x !()*Vml in .30 ml aliijuots) were cultured in Eagle's me<!iuni {F-15 CJrand Klancl Biologicid Co.) containing 10 ' M 2-mercaptoetliaTiot and coiuaiiaxalin A (Sigma Chi-mical (^o.) at a final concentration of 5 Mg/ml. The culture mediuui contained
Cellular Immunology, 1988
We earlier demonstrated that treatment of C57BL/6 mice bearing a syngeneic tumor, LSA, with 1,3-bis(2-chloroethyl)-1 nitrosourea (BCNU) resulted in over 90% survival of the mice, and 100% of the cured mice rejected secondary rechallenge with the homologous tumor but not with a heterologous syngeneic tumor such as EL-4. In the present study we investigated whether the host's immune system was also essential for successful chemotherapy with BCNU. It was observed that BCNU treatment was effective only in normal tumor-bearing mice (100% survival) but not in irradiated or nude tumor-beating mice (0% survival), thereby suggesting that the immune system, particularly the T cells, was essential for effective treatment with BCNU. Since BCNU-cured mice lack demonstrable T suppressor (Ts) cells, these mice were next used as a model to investigate the phenotype of the T cells mediating tumor rejection. It was observed that L3T4+ (CD4+) or Lyt-2+ (CD8+) T cells from BCNU-cured mice could provide significant protection (80 and 40% survival, respectively) in irradiated or nude mice but not in normal mice. It was also observed that BCNU-cured LSA mice elicited tumor-specific delayed-type hypersensitivity (DTH) reaction, while, normal mice or LSA tumor-bearing mice failed to elicit DTH reaction. Also, only L3T4+ but not Lyt-2+ T cells from BCNU-cured mice when adoptively transferred into nude mice could elicit a DTH reaction. The present study suggests that for effective chemotherapy against a syngeneic tumor, with a tumoricidal drug such as BCNU, the presence of L3T4+ and Lyt-2' T cells in the host is essential. o 1988 Academic mess, I~C.
The use of cytotoxic T cells in the regulation of tumour growth in syngeneic mice
Cancer Immunology Immunotherapy, 1984
Normal C57BL/6 (B6) spleen cells were cultured with syngeneic EL4 tumour cells, expanded in IL2-containing medium, and tested for anti-tumour activity in vitro and in vivo. The activated cells were highly cytotoxic for EL4 and to a lesser degree killed syngeneic B6 blasts and allogeneic (D2) P815 tumour cells. B6 or BDF1 mice that received these cultured cells by IP injection cleared 125IUdR-labelled EL4 cells faster than untreated mice. However, this enhanced clearance was evident only 7-12 days after injection. Since the injected cells had a short half-life (< 10% remaining after 48 h) the effect of these cells in vivo was most probably due to the activation of the host's immune system. Mice that received cultured cells survived significantly longer than untreated mice following a lethal dose of EL4 cells. Cultured cells were much more effective in prolonging survival when used in conjunction with cyclophosphamide (CY). In animals receiving either cultured cells with or without CY or CY alone tumour clearance was markedly enhanced 7-12 days after injection. When challenged with a small dose of EL4 tumour cells (1 x 104 SC per mouse) three of ten B6 mice treated with B6 anti-EL4 cultured cells were able to survive indefinitely. The frequency of CTL precursors to EL4 from the spleen cells of these surviving animals was about five-fold higher than that of normal spleen cells. Furthermore, CTL derived from primed spleen cells were more specific for EL4 than those derived from normal spleen cells.
International Journal of Cancer, 1978
Experiments were performed to test the effect of xenogeneic (fetal calf) serum (FCS), as compared to syngeneic mouse serum (SMS) on the generation in culture of specific cytotoxic lymphocytes (CL) against syngeneic tumors. Sensitization in FCS against 3LL tumor cells resulted in CL cross-reacting with 8-16 tumor cells and vice verso. Anti-syngeneic fibroblast CL also cross-reacted with 3LL. Such cross-reactivities were shown to be derived from CL directed against FCS determinants. In contrast, sensitization in the presence of SMS resulted in CL directed against tumor-specific antigens. Anti-3LL generated in SMS lysed 3LL targets but not 8-16. and anti-8-16 lysed 8-16 but not 3LL. The two types of CL had two distinct reactivities in vivo. Anti-3LL CL generated in FCS enhanced tumor growth in vivo, whereas antiJLL CL generated in SMS had an inhibiting effect on the growth of tumor cells. These results indicate that the application of syngeneic serum during in vitro sensitization against syngeneic tumors may open up new possibilities for the analysis of tumor-specific antigens and for eliciting specific immune reactions against such antigens.
Effect of tumor cells on the generation of cytotoxic T lymphocytes in vitro
European Journal of Immunology, 1977
Medi-lCenter. Dumam'and lmmunolow Effect of tumor cells on the generation of cytotoxic T lymphocytes in vitro 1. Accessorv cell functions of mouse tumor cells in the Division of Immunology, Duke University generation of cytotoxic T lymphocytes in vitro: replacement of adherent phagocytic cells by tumor cells Branch, National Cancer Institute, National Institutes of Health, Bethesda' or 2-mercaptoethanol* In agreement with previous reports, the primary in vitro response to alloantigens has been shown t o be dependent o n the presence of m a c r e phages (Mphs). Splenocytes extensively depleted of adherent phagocytic cells did not generate cytotoxic T lymphocytes, and this activity could be completely restored by small numbers of adherent peritoneal cells (accessory cells). Either P388D1 (Mph-like tumor), P388 ("null" tumor) or P8 15 (mastocytoma) tumor cells, or 2-mercaptoethanol, could completely replace the accessory function normally mediated by accessory cells. These tumor cells did not nonspecifically "enhance" the cytotoxic activity generated with normal nondepleted spleen cells. The restored cultures maintained killing specificity t o H-2 targets which was mediated by effector T cells as shown by sensitivity t o anti-@ and complement. Therefore, Mphs seem not t o be the sole cells capable of mediating an accessory function in a primary response t o alloantigens in vitro.
European Journal of Immunology, 1976
Antigenic specificity of the cytolytic T lymphocyte (CTL) response to murine sarcoma virus-induced tumors I. Preferential reactivity of in vitro generated secondary CTL with syngeneic tumor cells* Incubation of spleen cells from mice having rejected a Moloney sarcoma virus (MSV)-induced tumor with syngeneic irradiated lymphoma or sarcoma cells bearing MSV-associated antigens in secondary mixed leukocyte-tumor cell cultures (MLTC) resulted in the generation of highly active cytolytic T lymphocytes (CTL) specifically directed against syngeneic target cells bearing MSV-associated antigens. When MSV-immune spleen cells from C57BL/6 (H-2b) and BALB/c (H-2d) mice were compared with respect to their ability t o generate CTL in syngeneic secondary MLTC, it was found that both lymphoid cell populations were equally able t o mount an anamnestic CTL response to MSV-associated antigens as assessed by a short-term 51Cr release assay. However, quantitative analysis of the activity of both CTL populations on either H-2b or H-2d tumor cells indicated that target cells sharing the same major histocompatibility complex (MHC) as the effector cells were lysed 10-to 100-fold more efficiently than allogeneic target cells. As suggested by the results of inhibition experiments using mixtures of 51 Cr-labeled and unlabeled target cells, preferential lysis of syngeneic versus allogeneic tumor cells might be related to the establishment of effective adhesions between the former and CTL. Direct evidence for the role of MHC in determining the antigenic specificity of CTL directed against MSV-associated antigens was provided by results obtained using MSV-immune spleen cells from congenic resistant mice. Furthermore, studies of the response of F , (H-2b/d) hybrid mice showed that stimulation of immune spleen cells with tumor cells from one parental strain or the other in secondary MLTC resulted in the generation of CTL capable of lysing tumor target cells of the same parental strain as the stimulating cells, but not of the other. The results thus suggested the presence of two sets of CTL precursor cells in F, MSV-immune spleens, each set responding exclusively to tumor antigens associated with only one of the two parental phenotypes.
Une nouvelle approche pur l'induction de cellules T cytotoxiques specifiques in vivo
Res Immunol, 1990
The induction of specific cytotoxic T lymphocytes (CTL) is one component in the immune response which can effectively protect the host against the progression of many viral infections. CTL are also known to play an important role in immune defence against tumour growth. CTL induction is dependent the presence of the specific antigen, appropriately presented, and interleukin-2 (IL2), provided by T helper lymphocytes. We studied the specific CTL response induced by tumour cells transfected with murine IL2. Our results show that tumour cells manipulated to secrete IL2 induce an improved specific anti-tumour response which results in tumour rejection in mice. To further investigate the effect of IL2 on the CTL response_ to_ different_.. _. .. _~nti~, ,n~.., . . . . . , u,,~..,. introduced synthetic peptides into IL2-secreting tumour cells and determined the specific CTL induction in syngeneic mice immunized with these cells. We report here that such IL2-secreting cells can effectively prime peptide-specific CTL in vivo. Our data are relevant to immunotherapy and vaccine develop° ment and open up the possibility that autologou s cells, manipulated to secrete IL2 and located with one or a cocktail of peptides, could be used to stimulate a specific CTL response.