Biomedical subjects

Jonathan Kipnis

Publications and source records attributed to Jonathan Kipnis.

25 records · Page 2Linked to original sources

PubMed2003

Therapeutic vaccination for closed head injury.

Closed head injury often has a devastating outcome, partly because the insult, like other injuries to the central nervous system (CNS), triggers self-destructive processes. During studies of the response to other CNS insults, it was unexpectedly discovered that the immune system, if well controlled, provides protection against self-destructive activities. Here we show that in mice with closed head injury, the immune system plays a key role in the spontaneous recovery. Strain-related differences were observed in the ability to harness a T cell-dependent protective mechanism against the effects of the injury. We further show that the trauma-induced deficit could be reduced, both functionally and anatomically, by post-traumatic vaccination with Cop-1, a synthetic copolymer used to treat patients with multiple sclerosis and found (using a different treatment protocol) to effectively counteract the loss of neurons caused by axonal injury or glutamate-induced toxicity. We suggest that a compound such as Cop-1 can be safely developed as a therapeutic vaccine to boost the body's immune repair mechanisms, thereby providing multifactorial protection against the consequences of brain trauma.

Animals↗

PubMed2002

Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system.

The ability of rats or mice to withstand the consequences of injury to myelinated axons in the CNS was previously shown to depend on the ability to manifest a T cell-mediated protective immune response, which is amenable to boosting by myelin-specific T cells. Here we show that this ability, assessed by retinal ganglion cell survival after optic nerve injury or locomotor activity after spinal cord contusion, is decreased if the animals were immunized as neonates with myelin proteins (resulting in their nonresponsiveness as adults to myelin proteins) or injected with naturally occurring regulatory CD4(+)CD25(+) T cells immediately after the injury, and is improved by elimination of these regulatory T cells. In nude BALBc mice replenished with a splenocyte population lacking CD4(+)CD25(+) regulatory T cells, significantly more neurons survived after optic nerve injury than in nude mice replenished with a complete splenocyte population or in matched wild-type controls. In contrast, neuronal survival in wild-type BALBc mice injected with CD4(+)CD25(+) regulatory T cells immediately after injury was significantly worse than in noninjected controls. These findings suggest that the ability to cope with the sequelae of a CNS insult is affected unfavorably by nonresponsiveness to myelin self-antigens and favorably by conditions allowing rapid expression of an autoimmune response. The regulatory T cells might represent an evolutionary compromise between the need to avoid autoimmune diseases and the need for autoimmunity on alert for the purpose of tissue maintenance.

Adoptive Transfer↗

PubMed2002

Myelin specific Th1 cells are necessary for post-traumatic protective autoimmunity.

Myelin-specific encephalitogenic T cells, when passively transferred into rats or mice, cause an experimental autoimmune disease. Previous studies by our group have shown that (a) the same cells also significantly reduce post-traumatic degeneration in these animals after injury to the central nervous system, (b) this beneficial autoimmunity is a physiological response, and (c) animals differ in their ability to resist injurious conditions, and the ability to resist post-traumatic degeneration correlates with resistance to the development of an autoimmune disease. Here we show that optic nerve neurons in both resistant and susceptible rat strains can be protected from secondary degeneration after crush injury by immunization with myelin basic protein emulsified in complete or incomplete Freund's adjuvant. We provide evidence that potentially destructive autoimmunity (causing autoimmune disease) and beneficial autoimmunity (causing improved neuronal survival) both result from activity of the same myelin-specific, proinflammatory Th1 cells. We further show that following passive transfer of such Th1 cells, the expression of their beneficial potential depends on the activity of an additional T cell (CD4(+)) population. By identifying the additional cellular component of autoimmune neuroprotection, we may be able to take meaningful steps toward achieving neuroprotection without risk of accompanying autoimmune disease.

Animals↗

PubMed2002

Autoimmunity on alert: naturally occurring regulatory CD4(+)CD25(+) T cells as part of the evolutionary compromise between a 'need' and a 'risk'.

Autoimmunity, at least in the central nervous system (CNS), is not only an outcome of immune system malfunction, but is the body's own protective mechanism against destructive self-compounds. Likewise, the naturally occurring regulatory CD4(+)CD25(+) T cells have a physiological function, and are not merely an evolutionary adaptation to suppress self-reactive T-cell clones that escaped deletion in the thymus. We postulate that the regulatory T (Tr) cells are the product of an evolutionary compromise between the need for autoimmunity on alert for tissue maintenance and the need to control autoimmunity to avoid autoimmune disease. In the event of an insult to the CNS, the balance between self-reactive (effector) T cells and Tr cells determines the time of onset, the intensity and the duration of the autoimmune response. This response might thus represent an adaptive mechanism, which is optimal for day-to-day maintenance, but insufficient in extreme cases of CNS damage or failure of regulation. Downregulation or upregulation of CD4(+)CD25(+) Tr cells might be a way to achieve better protection from neurodegenerative conditions induced by self-destruction or avoid autoimmune inflammatory disease development, respectively.

Animals↗

PubMed2002

Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders.

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other. One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases. We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a 'universal antigen' by weakly activating a wide spectrum of self-reactive T cells.

Animals↗

PubMed2002

Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: a paradigm shift.

Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.

Animals↗

PubMed2002

Resistance of retinal ganglion cells to an increase in intraocular pressure is immune-dependent.

PURPOSE: Glaucoma is widely accepted as a neurodegenerative disease in which retinal ganglion cell (RGC) loss is initiated by a primary insult to the optic nerve head, caused, for example, by increased intraocular pressure (IOP). In some cases, the surviving RGCs, despite adequate IOP control, may continue to degenerate as a result of their heightened susceptibility to self-destructive processes evoked by the initial damage. In animal models of mechanical or biochemical injury to the optic nerve or retina, a T-cell-mediated immune response evoked by the insult helps to reduce this ongoing loss. The current study was conducted to find out whether the ability to resist the IOP-induced loss of RGCs in a rat model is affected by the immune system. METHODS: The ocular veins and limbal plexus of rats of two strains differing in their resistance to experimental autoimmune encephalomyelitis (EAE) and in their ability to manifest a beneficial autoimmune response were laser irradiated twice to induce an increase in IOP. The pressure was measured weekly, and RGC losses were assessed 3 and 6 weeks after the first irradiation. To verify the existence of a relationship between the immune system and RGC survival, we assessed neuronal survival in Sprague-Dawley (SPD) rats devoid of mature T cells as well as after transferring splenocytes from Fisher rats, an EAE-resistant rat strain capable of manifesting T-cell-mediated neuroprotection, to rats of a major histocompatibility complex (MHC)-matched EAE-susceptible strain (Lewis), in which the ability to manifest such protective immunity is limited. RESULTS: Both 3 and 6 weeks after the increase in IOP was initiated, the number of surviving RGCs in SPD rats, a strain in which a beneficial autoimmune response can be evoked spontaneously, was significantly higher than in Lewis rats. Moreover, in SPD rats that were thymectomized at birth, the number of surviving RGCs after an increase in IOP as adults was significantly diminished. Passive transfer of splenocytes from Fisher rats to Lewis rats significantly reduced the IOP-induced loss of RGCs in the latter. CONCLUSIONS: In rats of different strains, a similar increase in IOP results in differing amounts of RGC loss. This disparity was found to correlate with immune potency. These findings may explain why patients with glaucoma experience different degrees of visual loss after pressure reduction, even when the severity of the disease at the time of diagnosis is similar. The results have far-reaching prognostic and therapeutic implications.

Animals↗