Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1981-07-02
1985-09-10
Rosen, Sam
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
A61K 3528
Patent
active
045405743
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a water soluble fraction from bone marrow having biological activities including that of controlling the immune reactions of a host against allogeneic cells or tissue, particularly host versus-graft reaction (HVGR) and so-called graft versus-host reaction (GVHR) in transplantation of allogeneic incompatible bone marrow, of promoting engraftment of allogeneic marrow in vivo and of protecting the host against irradiation and the consequences of irradiation.
It has already been published that viable bone marrow cells were capable of controlling immunological reactions (HVGR and GVHR) ensuing when immunogenetical different bone marrow is transplanted into a lethally irradiated host (immunity). More particularly, it has already been found that bone marrow cells were capable of facilitating engraftment of foreign cells or tissue (allogeneic or xenogeneic in a host) when administering them to said host according to a determined protocol or regimen including a total body irradiation procedure, the latter being aimed at destroying the host's own immune system and at facilitating the substitution for it of an immune system of foreign origin.
More particularly, it has been found that the treatment of mice, which comprises administering to them rat bone marrow cells, then subjecting them shortly thereafter to lethal total body irradiation (TBI) and subsequently readministering new bone marrow cells, resulted in remarkable protection of said mice against radiation injury, also, when the bone marrow cells administered after TBI were of xenogeneic origin (i.e. rat), facilitation of marrow engraftment and induction of a persisting xenogeneic (rat) chimerism in said mice occurred ("A new pre-irradiation conditioning regimen which protects against radiation injury and facilitates engraftment of xenogeneic bone marrow"-Walter Pierpaoli & Georges J. M. Maestroni, Scand. J. Haematol. (1979), 22, 165-172.
The operational procedure preceding TBI was, and will hereafter be in relation to the invention, be designated by "preconditioning" while the designation "post-conditioning" referred to will also hereafter refer to the administration of material of bone marrow origin after TBI.
On utilizing the model of xenogeneic (rat to mouse) marrow transplantation, it was established that the critical factors for success included a sufficient number of viable bone marrow cells before and after TBI, the timing and the route of inoculation; each of these had to be correctly poised to assure protection against secondary disease, long term survival and the development of chimerism.
The present invention stems from the discovery that the viable marrow cells were exerting this strikingly favorable effect via synthesis and/or secretion, in the host, of components facilitating engraftment of the transplanted incompatible marrow after lethal TBI.
Particularly, it has been found that the abovesaid favorable effect can be attributed to a water-soluble biolocigally active fraction obtainable from the physiological inter-cellular medium of bone marrow of any mammalian animal, particularly, after separation therefrom of the bone marrow cells themselves.
This discovery was all the more unexpected as the physiological inter-cellular medium (bone marrow supernatant SN) as such does not exhibit substantial activity, unless special care is taken to avoid inactivation of the biologically active fraction. Reproducible activity in a testing system as hereabove defined and as said biologically active fraction tends to be inactivated when the pH is neutral or tends to fall below 7.0 and contains both inhibitors and activators of bone marrow functions.
The water-soluble biologically active fraction according to the invention which is obtainable from the physiologically inter-cellular medium of bone marrow has the following characteristics:
it is substantially free of inhibitors which have molecular weights essentially lower than about 30 000;
it is lyophilizable without loss of biological properties;
it exhibits the hereafter defined diolo
REFERENCES:
patent: 3526697 (1970-09-01), Livingston
patent: 3676551 (1972-07-01), Thuillier
Maestroni Georges
Pierpaoli Walter
Cellena (Cell Engineering) A.G.
Choay S.A.
Rosen Sam
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