Table 5.

Major experimental attempts to produce an animal model of paraneoplastic neurological disease associated with antibodies targeting intracellular neuronal antigens.

References	Antigen targeted	Species	Method	Study duration	Outcome
Graus et al. (73)	Yo	Guinea pigs	Intraventricular infusion of anti-Yo or normal IgG	15 days	Uptake of both anti-Yo and normal IgG by Purkinje cells on day 16 but not at days 22 and 45. No observed Purkinje cell death or neurological change in animals
Tanaka et al. (74)	Yo	Mice	Intracranial injection of human anti-Yo IgG with and without complement or activated monocytes	Up to 50 h	Uptake of human anti-Yo IgG by Purkinje cells. No detected Purkinje cell loss
		Mice	Immunization with recombinant Yo protein	15 days for pathology, 3 months for observation	Development of high antibody titers No definite uptake of antibody by Purkinje cell
		Rats	Intraventricular injection	1 week	No Purkinje cell loss. Brains not studied for antibody uptake by neurons.
Tanaka et al. (75)	Yo	Mice	Immunization of multiple mouse strains with recombinant Yo protein	>2 months	No Purkinje cell loss or ataxia Strong peripheral anti-Yo production Brains not studied for uptake by neurons.
Tanaka et al. (76)	Yo	Mice	Injection of human anti-Yo IgG into occipital lobes	50 h	Antibody uptake by Purkinje cells. No Purkinje cell loss
		Mice	Injection of mouse recombinant anti-Yo IgG into mouse brain parenchyma	3–4 months	High titers of anti-Yo antibody. No neurological abnormalities No Purkinje cell loss Brains not studied for antibody uptake by neurons
		Mice	Adoptive transfer) of lymphocytes from mice immunized with recombinant Yo protein with and without recombinant anti-Yo antibodies	1 month	No neurological abnormalities No Purkinje cell loss Brains not studied for antibody uptake by neurons.
		SCID Mice	Adoptive transfer of peripheral mononuclear cells from a patient with anti-Yo antibody	1 month	No neurological abnormalities No Purkinje cell loss Attempts to detect intraneuronal IgG not described
Greenlee et al. (77)	Yo	Rats	Intraperitoneal injection of human anti-Yo antibody following blood-brain barrier disruption	4 days	Anti-Yo IgG uptake by Purkinje cells. No evidence of Purkinje cell death No neurological abnormalities
Sillevis Smitt et al. (78)	Hu	Mice	Passive intravenous transfer of human anti-Hu IgG	48 h	No evidence of anti-Hu IgG in brains of animals perfused to remove intravascular IgG No evidence of antibody uptake by neurons in perfused brains)a
		Mice, Rats, Guinea pigs	Immunization with HuD recombinant protein	Up to 21 weeks	High serum antibody titers: No evidence of penetration of IgG into brain parenchyma or neurons in brains perfused to remove intravascular IgG
Tanaka et al. (79)	Yo	Mice	Immunization of female mice with recombinant protein; evaluation of offspring to detect transplacental passage of antibody to offspring with undeveloped blood-brain barriers	At birth and later	No Purkinje cell loss at birth No ataxia in newborn animals allowed to mature Brains not studied for antibody uptake.
Sakai et al. (80)	Yo	Mice	Immunization of mice with recombinant PCD17 protein generated using anti-Yo antibody (81)	1 year	Generation of high serum antibody titers. Presence of IgG in Purkinje cells of immunized mice, No identified Purkinje cell death or neurological abnormalities
Sakai et al. (82)	Yo	Mice	Immunization with DNA encoding recombinant PCD17 protein	Up to 1 year	Generation of antibody response which could lyse syngeneic myeloma cells pulsed with H-2K-restricted PCD17 peptide. No Purkinje cell loss or neurological abnormality Brains not studied for antibody uptake.
Pellkofer et al. (83)	Ma1		Adoptive transfer of lymphocytes from syngeneic rats immunized with recombinant Ma1 protein	9 days	Meningeal and perivascular inflammatory changes. No evidence of neuronal injury
Sakai et al. (84)	Yo	Mice	Immunization with recombinant yeast expressing recombinant (pcd17) Yo antigen	6 months	Generation of antibodies reactive with Purkinje cells and of T lymphocytes sensitized to pcd17 No clinical signs or Purkinje cell loss. Brains not studied for antibody uptake.

This study contained important controls for the detection of adventitious entry of antibodies into neurons in post mortem tissue sections.