Cell‐mediated cell lysis <i>in vitro</i>: genetic control of killer cell production and target specificities in the mouse

Nabholz, Markus; Vives, Jordi; Young, H.; Meo, Tommaso; Miggiano, V.; Rijnbeek, Anne‐Marie; Shreffler, Donald C.

doi:10.1002/eji.1830040514

Cited by 224 publications

(103 citation statements)

References 28 publications

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“…Differential cytotoxicity against non-H-2 antigens was not detectable in this system (12), and species-specific antigens played a very minor role, if any. Thus, the specificity of xenogeneic cytotoxic effector cells parallels that of allogeneic effector cells (31)(32)(33)(34). The absence of detectable cytotoxicity against/-region determinants, which can be found in sensitive allogeneic systems (35)(36)(37)(38), may be due to the relative inefficiency of the xenogeneic cytotoxicity system.…”

Section: Discussionmentioning

confidence: 94%

Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.

Lindahl¹,

Bach²

1976

The Journal of Experimental Medicine

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Xenogeneic lymphocytes can induce proliferative responses in the mixed lymphocyte culture (MLC) ~ which are as strong as those induced by allogeneic lymphocytes (1). It is impossible to determine directly which lymphocyte antigens stimulate the xenogeneic MLC response. The recently described "primed lymphocyte typing" (PLT) assay (2) has made it possible to determine indirectly the genetic control of xenogeneic MLC. Sensitization in a mixed lymphocyte culture positively selects for memory cells which give a rapid secondary response upon restimulation with cells from the initial stimulator (3, 4). Studies in human families (2, 5-7) showed that restimulation is caused by the same LD determinants of the major histocompatibility complex (MHC) that induce primary MLC responses.In this paper we present studies of human lymphocytes which were sensitized to cells of a single mouse strain and restimulated with cells from a variety of strains. By choosing combinations of primary and secondary stimulator which shared only certain parts of their genetic material, we could assay the relative importance of non-H-2 and various H-2 antigens for activation of human lymphocytes. The results suggest that the same antigens are important in allogeneic and xenogeneic MLC reactions. The ability of human leukocyte subpopulations to respond in xenogeneic MLC further suggest that the cellular requirements of allogeneic and xenogeneic MLC responses are the same. Materials and MethodsMice. Mice used in this study were bred in our own colony or purchased from The Jackson Laboratory, Bar Harbor, Maine (Table I).Spleen Cells. Spleens were removed aseptically into phosphate-buffered saline (PBS) (Dulbecco's, Ca 2+ and Mg 2÷ free, Grand Island Biological Company, Grand Island, New York), and the cells were pressed through a stainless steel wire screen. The suspension was allowed to settle and big sediments removed. Erythrocytes and dead cells were removed by hypotonic shock (8); the cells were resuspended in PBS and viable cells counted in eosin.

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Section: Discussionmentioning

confidence: 94%

Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.

Lindahl¹,

Bach²

1976

The Journal of Experimental Medicine

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“…12 In our study, responder cells were splenocytes obtained from C57BL/6 mice and the stimulators were MMC inactivated LLC tumor cells. The ratio of responder/stimulator is 10:1 according to predetermined results.…”

Section: Generation Of Tumor Specific Ctl By Mltc In Vitromentioning

confidence: 99%

A simple and effective method for cancer immunotherapy by inactivated allogeneic leukocytes infusion

Guo

Zhou

et al. 2008

Intl Journal of Cancer

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Allogeneic mixed leukocytes reaction has been reported to activate vast numbers of T lymphocytes and produce large amounts of type 1 cytokines that are linked to an initiation of antitumor immunity. Using poor immunogeneic B16-F10 and Lewis lung carcinoma (LLC) tumor model, we evaluated the effects of inactivated allogeneic leukocytes infusion (ALI) on the generation of antitumor immune response, as well as its effect on the primary and metastatic tumor. Allogeneic response promoted the generation of both specific and nonspecific antitumor immunity in an in vitro mixed lymphocytes-tumor cell culture system. Introveinous infusion of mitotically inactivated allogeneic leukocytes resulted in increased type-1 cytokines (including IL-2 and IFN-c) release, proliferation of various lymphocyte subsets, and generation of both specific and nonspecific antitumor immune response. As a result of such immune response, ALI caused a delayed tumor growth and a prolonged survival in established B16-F10 melanoma model. In LLC pulmonary spontaneous metastases model, ALI treatment significantly reduced postoperative tumor metastasis as the lung weights were far smaller than control group (0.16 vs. 0.34 g). Furthermore, after primary tumor resection and ALI treatment, 62.5% mice obtained long-term survival (>120 days) and there were no tumor growths in these mice when they were rechallenged with the same tumor. These experiments demonstrate that inactivated ALI could activate innate and adoptive antitumor immune response. It would be a simple, effective and secured method for cancer immunotherapy. ' 2008 Wiley-Liss, Inc.Key words: cancer; immunotherapy; alloantigen; metastasis Allogeneic transplantation (including heametopoietic stem cell transplantation) has been used as a successful therapeutic modality for various diseases, including malignancies. 1 Nevertheless, there is always a major limitation in the allogeneic transplantation: either host vs. graft (HVG) or graft vs. host (GVH). With a clear manifestation of the mechanisms of transplantation immunology, it is well recognized that alloantigen, a potent immunostimulator, elicits strong and rapid cellular and humoral immune responses, plays a key role in HVG or GVH. However, both HVG and GVH biology share several mechanisms that contribute to antitumor effects that occur outside of allogeneic transplantation, including IFN-g secreting type 1 T cells, 2 antigen presenting cells (APCs) activation, 3 and fas-and perforin-based cytolysis. 4 Therefore, it is possible to harness these characteristics as a therapeutic modality for malignancy.Actually, hematopoietic stem-cell transplantation (HSCT) is under study as a immunotherapeutic modality and achieve considerable effect in a wide range of hematologic and nonhematologic malignancies. 1,5 The basis of this treatment rests on an immune mechanism called the graft-versus-leukemia or graft-versus-tumor effect. Presumably, alloreactive T cells (CD4 and CD8 T cells) in the allograft participate in these phenomena, but the relevant antige...

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“…The one-way cross-reactivity which sometimes occurs (14,35) can then be understood only if one takes into account that the frequencies of CTL.P reactive in different combinations differ. The C3H cells which react to both DBA/2 and C57BL/6 thus constitute a larger fraction of the pool of C3H cells reactive to C56BL/6 than of the cells reactive to DBA/2, and it may therefore appear as if activation with C57BL/6 leads to more cross-reaction than activation with DBA/2.…”

Section: Assessments Of Proliferation and Cytotoxicmentioning

confidence: 99%

Histocompatibility antigen-activated cytotoxic T lymphocytes. II. Estimates of the frequency and specificity of precursors.

Lindahl

Wilson

1977

The Journal of Experimental Medicine

336

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Using limiting dilutions of responding cells in mouse mixed leukocyte cultures, we obtained direct estimates of the minimum frequency of precursors of cytotoxic T lymphocytes (CTL.P) for a variety of antigens. Depending on the strain combination, there were as many as 4-15 CTL.P reactive to DBA/2 among 10(4) lymph node cells. Taking into account that only 5-10% of peripheral T lymphocytes have the potential to develop into cytotoxic T lymphocytes (CTLs) (6), this implies that at least 1-2% of all CTL.P are responsive to any given H-2 haplotype difference. Precursors of cytotoxic cells thus have the same high frequency of cells reactive to alloantigens of the major histocompatibility complex as found among proliferating cells in graft-vs.-host reactions and mixed lymphocyte interactions. The frequencies of CTL.P reactive to xenoantigens (rat) or trinitrophenyl-modified self were less than half the frequency of alloreactive CTL.P. A minority of the CTL.P specific for one H-2 haplotype were also reactive to a third party H-2 haplotype, presumably on the basis of recognition of shared determinants. By dilution of sensitized cells from single microcultures, it was shown that a single CTL.P undergoes a minimum of three to four cell divisions and generates at least 8-16 CTLs after antigenic activation.

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Cell‐mediated cell lysis in vitro: genetic control of killer cell production and target specificities in the mouse

Cited by 224 publications

References 28 publications

Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.

Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.

A simple and effective method for cancer immunotherapy by inactivated allogeneic leukocytes infusion

Histocompatibility antigen-activated cytotoxic T lymphocytes. II. Estimates of the frequency and specificity of precursors.

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