BXD recombinant inbred mice represent a novel T cell–mediated immune response tumor model

Abstract

To develop a better animal model for studying the effects of the host environment in neoplasia, we injected various genetically well-characterized H-2 d RI strains of BXD mice with syngeneic breast cancer cells (TS/A) and monitored the growth of tumors over time. There was a marked difference in the growth of the implanted breast cancer cells among the 14 BXD RI strains, with 4 patterns of tumor development being observed: in type I, the implanted tumor cells grew rapidly in the first 2 weeks, necrosis of the tumors was observed and metastases to the intestinal lymph nodes and pancreas was observed, causing death; in type II, the implanted tumor cells grew slowly and attained a size after day 50 that required killing the animal, with tumor necrosis being rare and metastases absent; in type III, the implanted tumor cells grew initially but underwent a slow decline after 4 weeks; and in type IV, the implanted tumor cells failed to Characterization of the effect of the host environment on the development and progression of tumors has proven difficult due, in part, to the lack of informative models. The immune surveillance system, which is thought to play a key role in determining susceptibility or resistance to tumor growth, shows considerable variation among individuals. Although immunodeficient nude and SCID mice are useful tools for the characterization of the role of the host environment in the development and progression of human-derived tumors, 1,2 the lack of an intact immune system in these mice results in an incomplete picture of the potential mechanisms involved and their relative contribution to tumor growth. Comparative analysis of implanted syngeneic TS/A tumor cells in C57BL/6 mice, which are resistant to implanted tumors, and DBA/2 mice, which are susceptible, is a good model for the dissection of the host immune response to tumors but is limited by the lack of response diversity. [3][4][5] The genetically well-characterized BXD RI strain of mice was derived by intercrossing F 2 mice derived from DBA/2 and C57BL/6 mice for more than 20 generations to fix homozygous loci. These strains exhibit a broad spectrum of traits, including diversity in the types and intensity of the immune responses. 6 -12 The availability of these mice therefore presented an opportunity to develop an alternative model to analyze the mechanisms that determine the immune response to tumor cells. BXD mice have been used for genetic mapping of disease susceptibility 13,14 and for studying the development of the nervous system 15-17 and alcohol abuse. 6,18 Several investigators have recognized the advantage of using these mice to identify both MHCrelated and non-MHC-related genetic loci that affect the shaping of the repertoire and the function of the immune system. 7,13,19 -21 Waters et al. 22 utilized these mice to show that the genetic restriction involved in KLH antigen-specific proliferation maps to the mls gene on chromosome 1. Scalzo et al. 20 showed that the resistance of mice to lethal infection by MCMV is associated ...

Immunohistochemistry in the evaluation of neovascularization in tumor xenografts

“…An allograft from the syngeneic breast cancer cell line (TS/A) derived from a mammary adenocarcinoma that arose spontaneously in a BALB/c female mouse was also used. These latter cells (TS/A) were implanted in a BXD mouse, a genetically well-characterized animal model for studying the host immune response to neoplasia (Grizzle et al 2002). Normal lung tissues from corresponding athymic mice and BXD RI mice also were processed as control samples.…”

Age-related thymic involution in C57BL/6J × DBA/2J recombinant-inbred mice maps to mouse chromosomes 9 and 10

“…We have concomitantly observed that, at 12 months of age, the female B Â D RI strains with a slow rate of thymic involution also exhibited low tumor growth followed by regression of the tumor and an increased production of IFN-g in response to the TS/A breast tumor cells. 39 These results therefore suggest that identification of the genetic loci influencing the onset and rate of age-related thymic involution may be relevant to age-related immune defects and other associated diseases, such as cancer. We are currently analyzing the gene expression data and establishing F2 and congenic mice to narrow down the intervals of the QTL mapping results.…”

Thymocyte-Intrinsic Genetic Factors Influence CD8 T Cell Lineage Commitment and Affect Selection of a Tumor-Reactive TCR

“…1a) was correlated with a lower resistance to growth of P1A-expressing tumors (results not shown). Whether differences in the efficacy of CD8 T cell selection also contribute to the higher susceptibility of DBA/2 as compared with C57BL/6-based mice in other transplanted tumor models (46) remains to be addressed.…”