Passive transfer of allergic encephalomyelitis in rats: a tool for drug mechanism studies and detecting late-acting immunosuppressants

Abstract

• 1. A strategy is described for evaluating drugs against different phases in the development of an auto allergic disease, experimental allergic encephalomyelitis. It is based on a cell transfer technique whereby the disease is passively transferred with lymphoid cells from actively immunized donor rats to normal syngeneic rats = passive recipients. Drugs may be applied in vivo to either the cell donors or the cell recipients or to cells in vitro whilst in transit; their efficiency being determined by the severity of the passive disease (weight loss, paralysis) in the recipients.

• 2. Examples are given illustrating the application of these techniques to:

  • (a) evaluating the lymphocyte-deactivating activity of various nitrogen mustards in vitro;

  • (b) recognizing drugs, e.g. gold derivatives, clofazimine, etc. that are not conventional immunosuppressant (or cytostatic) agents which, when given to the recipient animals, may prevent the expression of the adopted disease;

  • (c) comparing some known immunosuppressants for potency, duration of action, etc.;

  • (d) demonstrating the versatility of cycloleucine, ICI-47,776, etc.

• 3. Some merits of the strategy are discussed vis a vis using the local graft-versus-host reaction in rats to search for new drugs.

Appendices

Appendix

Further comments by the third author (M Whitehouse)

Nearly half a century later, this report is finally in print after its inception by Brian Newbould in 1969.

In 1974 it was considered too biological for a pharmacological journal and too drug-oriented for an immunological journal. The editors of both these leading journals were not interested in the new concept implied in this quest for more logical drug design; particularly targeting potential pathophoric lymphocytes and controlling their pathogenic activities through a range of mechanisms e.g. anti-sensitisation or suppressing populations of sensitised leukocytes or their subsequent roles in inducing tissue injury. The advent of this journal Immunopharmacology 27 years ago has certainly made it easier to bridge the interface between immunopathology and pharmaceutics. We must be grateful to all those who made it happen and to the three publishers who successively sustained the journal after its launch in 1991.

An updated overview of EAE for drug evaluation

A reviewer kindly suggested some updates for using experimental auto allergic encephalomyelitis (EAE) as an animal model for multiple sclerosis (MS) (Constantinescu et al. 2011) and noted some limitations of this model (See Baxter 2007; Denic et al 2011; Lassman 2018). These are primarily based on the discrepancy between knowing the nature of the auto-antigen(s) used to trigger EAE in rodents (and other experimental animals) and the supposedly unknown entities that both trigger and sustain the clinical spectrum of MS.

Ebringer and his colleagues have recently indicated that an infection might trigger MS, particularly as a source of bacterial antigens, eg some derived from Acinetobacter, that may cross-react immunologically with human myelin (Ebringer 2015). This has prompted a search for classic and novel antibiotics targeted to control Acinetobacter baylyi infection including some traditional medicines sourced from Africa, Australia and India (Sirdaata et al 2015; Mandeville and Cock 2018; Cock and Cheesman 2018). But knowing the identity of an initiating agent may not be sufficient for treating established disease.

Several of the current therapies for MS (Broadley et al 2015) were developed after being shown to suppress EAE in animals. However some other treatments that effectively suppressed EAE development in animals have provided little or no clinical benefit for patients with MS. Yet others now used to treat MS have not been so effective in controlling EAE in animals at subtoxic doses eg dimethyl fumarate (DMF) effective in mice (Schultz-Topphoff et al 2016) but not in rats.

In summary, the EAE model certainly has limitations for validating new clinical agents to treat MS. But as used in this original study from UCLA, it does allow dissection of disease development and drug evaluation at each of the three stages (I–III).${\text{Antigen}\mathop{\rightarrow}\limits^{\rm I}}\,{\text{Sensitisation}\mathop{\rightarrow}\limits^{\rm II}}\,{\text{Auto-intolerance}\mathop{\rightarrow}\limits^{\rm III}}\,{\text {Neurological injury}}$