The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

Abstract

Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

Passive Immunization with Neutralizing Antibodies Interrupts the Mouse Mammary Tumor Virus Life Cycle

“…Mouse strains with genetic resistance to MMTV infection have been described. Several of these strains generate higher neutralizing titers after MMTV infection (17,39). Consistent with those studies we show here that passive immunoprophylaxis providing preexisting Abs before viral challenge can completely change the fate of a chronic infection.…”

“…Although in susceptible mice this chronic Ab response is unable to clear the virus infection, resistant mouse strains such as I/LnJ have evolved a strong neutralizing Ab response that controls chronic infection and prevents infection of the progeny (39). This is in agreement with the role of a strong neutralizing antibody response in interruption of the viral life cycle (17).…”

“…We have recently demonstrated that stronger mammary gland infection and virus transmission to the next generation occur in mice generating only low neutralizing-Ab titers upon MMTV challenge (17). These natural Abs were incapable of clearing the virus from infected lymphocytes but could prevent virus spread from lymphocytes to mammary epithelial cells and among epithelial cells in most mouse strains.…”

“…However it is unclear whether passively transferred systemic IgG is effective in preventing mucosal virus infection. We have recently demonstrated that induction of strong neutralizing Ab responses after virus infection did not influence infection of peripheral lymphoid organs but strongly inhibited mammary gland infection, tumor development, and virus transmission to the next generation (17). These observations raised the question of whether neutralizing Abs were able to prevent virus production and amplification in nonlymphoid tissue rather than initial infection of B and T lymphocytes and DC.…”

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

“…The rapid induction of neutralizing antibody can be a critical factor in limiting the spread of the extracellular infection [1][2][3]. This is achieved by direct antigen-driven differentiation of B cells into B blasts and then plasmablasts and plasma cells without going through an affinity maturation stage in germinal centers [4][5][6].…”