CA2069111A1 - Method of treating auto-immune diseases using gallium compounds - Google Patents

Abstract

Gallium is utilized in methods of treating macrophage mediated autoimmune diseases and in the treatment and prevention of resistance to transplantation.

Description

WO 92/04896 -1- 2 ~ ~ 9 ~ 1 1 PCT/~S9l/06802 METHOD OF TREATING AUTO-I~IUNE
DISEASES USING G~LLIUM COMPOUNDS

This application i6 a continuation-in-part application of United States Serial No. 586,491, filed September 21, 1990.
Field of the Invention This inventlon relates generally to methods of treating autoimmune diseases, and a method of treatment and prevention of resistance to transplantation by the use of gallium or a pharmaceutically acceptable salt thereof.
Backqround of the Invention Immunosuppressive agents activate or inhibit lymphocyte proliferation. Lymphocyte proliferation is due to the interaction between antigens, macrophages, T- and B-lymphocytes as well as certain chemicals. The presence of certain antigens may actiYate a particular T- or B-lymphocyte. Further, certain B-lymphocytes can be activated by active T-lymphocytes while others are independent of the T-lymphocyte~ and are activated only by antigens. Activated T-lymphocytes can cause macrophages to produce a molecule known as interleuXin-1 which in turn activates both T- and B-lymphocytes. Activated T-lymphocytes can also produce a molecule known as interleukin-2 which further induces T-lymphocyte activation. Additionally, chemicals can trigger activity in T- or B-lymphocytes. Immunosuppressive agent~
affect the complex interactions between the components o~
the immune system.
The imnune system defends against substances which can cause disease, however, it cannot distinguish between helpful and harmful foreign substances and destroys both.
Often times the immunological mechanisms become sensitized to some part of an individual's own body causing inter~er2nce with or even destruction of that p rt. The ability to distinguish between the body'~ own and antigens not from the body becomes impaired and the body begins to .. . . .

, -2- PCT/~lS91/068 destroy itself. The result 1~ an autoimmune disea~e. Some autoimmune disea~es in man are multiple ~clero~1~, type I
diabetes mellitu6, lupus erythematosus, and Grave~ di~ease.
Suppression of the lmmune systt!m in autoimmune di6eases i~
desirable in minimizing or limiting the aff2ct3 of the di~ea~e.
Circulating antibodies and cellular immune response~
are involved in the rejection of transplanted tissues and organs. Unless the donor is the identical twin of the recipient or is the individual himself, the recipient's lymphocytes recognize the transplant as not being its own and immediately responds to destroy it. The exceptions to this situation ~re transplants to non-vascularized areas, such as the cornea of the eye, where lymphocytes do not circulate and therefore are not sensitized ~nd do not prompt an immune response. It is difficult to suppress the immune reaction to prevent rejection of the transplant without severely damaging the patient in other ways.
It has been found that gallium, and gallium nitrate, n particular, are effective in treating disea6es mediated by macrophage cell lines, including macrophage/T cell/~ cell interactions and for the treatment and prevention of resistance to transplantation.
Gallium ha~ been known for many years to be useful in the treatment of calcium bone disorders. Gallium is a metal which belongs to the Group III A Elements of the Periodic Table. The metallic compounds usad, have, of course, a low order of tox~city and are pharmaceutically acceptable.
Prior U.S. Patents 4,529,593 issued July 16, 1985 to Warrell et al; 4,686,104 i~sued August 11, 1987 to Hockman et al.; and 4,704,277 issued November 3, 1987 to 80ckman et al. describe methods of preventing exce~sive loss of calcium from human bone by the ad~inistration of pharmaceutically acceptable gallium-containing compound~. The '593 patent teaches the use of pharmaceutically acceptable galllu~ ~alt~
to reduce the exces~lve loss of bone calcium. The patent spec~fically teaches the use o~ galliu~ to prevent or treat , W~92/04~96 disorder6 a6soc~ated wlth extensive 1065 of calcium from bons in humans by adminl~tering to the individu~l pharmaceutlcally acceptable gallium compound. Of specinl importance among the disorders which, may be thus treated are hypercalcemia, 06teopenia, osteoporosis, bone destruction due to metastasi~ from malignant tumors and hyperparathyroidism. Gallium ~alts which are disclosed to be of use include nitrate, citrate, and halide, preferably the chloride, car~on, acetate, tartrate, oxylate, oxide or hydrated oxide.
Loss of bone mass from increased bone resorption results in accelerated transfer of calcium into the blood.
This is the major cause of hypercalcemia. Diseases result when 6ignificant depletion of bone calcium occurs and the serum calcium level exercises dangerously. The therapeutic agent o~ choice, according to the aforementioned patent~, for treating this and many other bone disorder6 iB gallium, which decreases bone resorption and thereby maintains bone tissue calcium content.
U.S. Patent 4,303,363 discloses a method of cancer treatment which uses radioactive 67-gallium as a cytotoxic agent. -Heretofore, there has been no link between the treatment of ~one disorders and cancer by the use of gallium ;-~
and the treatment of autoimmune and immunosuppressant diseases.

Summar~ of the Inventlon The present invention relates to methods of tr~ating macrophage mediated autoimmune diseases, and a method o~
treatment and prevention of resistance to transplantation by the use of gallium or a pharmaceutically acceptable ~alt thereof.
~etailed Desc~ion ~f thÇ_p~awi~s Figures l(a) and l(b) graphically represent the e~fect of gallium ad~inistration following experimental allergic - enc2phalitis (EAE) induction;

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, . .. . . . . . . . .. .. . . .

W092/04896 ~i~ ?---ç~, 4 PCT/US91/06802 Figure 2 graphically repr~sents the effects of galliumto PEAT-specific T line cells during stimulation with PEAT
or Concanavalin A and antigen-presenting cells;
Figure 3 graphically represents a decline in the expression of I-A in macrophages of BALB/c mice with and without gallium; and Figure 4 graphically represents the prevention of diabetes by the administration of gallium.
Detailed Description of the Invention In accordance with the present invention, it is believed that gallium is effective in the treatment of autoimmune diseases involving various body systems: central nervous, cardiopulmonary, gastrointestinal, dermatological, endocrine, renal, reproductive, skeletal and the hepato-biliary systems. The wide reaching functionality of gallium indicate that it has promise as ~ therapeutic agent for many conditions and diseases heretofore not associated with gallium.
More specifically, the present invention relates to the use of gallium compounds in the treatment of autoimmune diseases which are mediated by macrophage cell lines including macrophage/T cell/B cell interaction. These diseases include multiple sclerosis, thyroiditis, type I
diabetes mellitus, Hashimoto's Disease, Graves Disease, lupus erythematosus, rheumatoid arthritis, sarcoidosis, Wegner's granulomatosis and leprosy. In the past, gallium compounds have been e~ployed in the tr~atment of disorders associated with bone tissue, and as a cytotoxic agent, but have not been administered for the treatment of the aforementioned autoimmune disease~. Further, in the present invention, gallium is utilized in the suppression of T-cell proliferation.
The following experiments were designed to show the administration and use of galliu~ for preventing and/or treating autoimmune diseases and to show the efficacy of galliuu in the resistance to transplantation. The experiments are shown in examples which are illustratiYe of , . . :. . - . , . " ~ .... " .. ., . . . .. , . , . .. . : . ~ ., - ... - ..

W O 92/04896 -5- 2 ~
-- ~ V ~ ~ 1 1 P ~ /US91/068n2 the pre6ent invention. The examples are not lntended to limit the ~cope of the lnventlon in any way.

E~ampl.e 1 ~ ffect ~f q~ um ~dminis~rati~n on expçri~ent~l allerqiç çncephalomYelitis rE:~F~.
This study demonstrates that the administration of galllum pravents the development of EAE and results in an antigen-specific suppression of the lyphocyte proliferative response. The animal model screens compounds for efficacy against multiple sclerosis.
Materials and Methods ~ . Male Lewis rats (8-12 wee~s of age) were purchased from Harland Sprague-Dawley (Indianapolis, IN).
The rats were divided into five groups.
Antiqens. Guinea pig MBP myelin basic protein (GPMEP) and rat MBP (RMBP) were prepared from 6pinal cords (Rockland, Inc., Gilbertsville, PA) by cholorform/methanol extraction. Human MBP (HuMBP) was prepared from cerebral cortex by cholorform/methanol extraction. The control antigen ovalbumin (OVA) wa~ obtained from Sigma (St. Loui8, MO), and ~urified protein derivative (PEAT) was from Parke- -Davis (Detroit, MI).
Gallium ~itrate. Ben Venue La~oratories, Bedford, Ohio was the source of a citrated solution of gallium nitrate, 500 mg/20 ml. Rats received in~ections of gallium as described in Figure la on days 1, 6, 13 and 20 relative to the induction o~ EAE. Group 1 animal~ received only ~aline;
al~ other6 received weekly injection~ of gallium a~ noted.
Group~ 3 and 5 received saline rather than gallium on day -1 . ' Induction of EAE. Rats received an intradermal injection into one hind footpad of guinea plg MBP (25 ug), combined with complete Freund'~ adjuvant (CFA) on day 0.
- All rats were ~onitored daily for clinical neurol~gic ~igns, which were scored as ~ollows: limp tail, 1+; ataxi~, 2+;
early or partial paraly~i~, 3~; full hind limb paralysi~, 4+

:
. .-W092/04896 ~ 6- PCT/US91/06802 deaths. Rats were sacrificed at the ti~e of severe paralysi~ or 21-38 days after ~;ensitization lf no clinical - ~igns appeared.
Hlstop,a~h~logi,ç ev~luation. Brains and spinal cords were removed and fixed in 10~ formalin, and 7-~m transverse sections of the thalamus, mesencephalon, and cerebellum-pons and longitudinal sections of the entire spinal cord were processed for hematoxylin and eosin staining. Histologic slides were assessed for the presence of perivascular mononuclear infiltrates and scored as follows: 1-10 lesions, 1+; 11-30 lesions, 2+; and greater than 30 lesions, 3+.
' Results Figures l(a) and l(b) graphically represent the effect of gallium administration prior to or following experimental allergic encephaliti (EAE) induction.
Clinical signs of EAE were ~cored as descri~ed in Figure l~a~. Rats who received 30 mg per kg on day 6 had the lowest clinical scores, irrespective of day -1.
CNS Histological Evaluations were performed on all rat~
as r~ported in Bitar et al. ~ell. Immunol. 112:364-370 (1988).
The rats received subcutaneous injections of 30 mg/kg gallium in tXe form of gallium nltrate beginning six days after induction of EAE with maintenance doses of 10 mg/kg on days 13 and 20. Controlled untreated rats progressed to maximu~ paralysis by day 13 as ~hown in Figure l(a), whereas gallium treated rats exhibited either no sign~ or ~inimal disease (partial left tail). Studies were subsequently undertaken to determine the ef~ect~ of dosage~ and t1ming of administration gallium on EAE. Gallium totaling 0-80 mg/kg was ac~inistered at weekly intervals beginning either be~ore or after induction of EAE as ~hown in Table 1. Mark~d suppr~ssion of EAE was demonstrated in all gallium treated (30-R0 mg/kg) animals. Maximum inhibition of clinical di~ease was ach~eved when 30 mg/kg was given on day 6, ancl ~aximal ~uppression of histopatholo~i~ chang~ occurred at the larg~st close of galliu~. No demonstrable adverse W092/04~96 7~ ~ PCT/U~91/068~2 clinical effect~ of gallium were notPd in any of thQ in YiYQ
BtUdieE~ .
The optimum timing for admini~tration ~f galllu~
following induction of EAE was determlned by injectlng 30 mgtkg as a single dose to the rats on day 3, 6, 9, or 12 after induction. Figure l(b) ~hows that gallium exerts its maximal suppressive effect when given on day 6, with a significant inhibitory effect also observable when administered on day 3 or 9. ]?ollowing compl~te recovery, rats from each group were reinjected with myelin ~a6ic protein (MEP) on day 28 and none developed EAE.

ExamPle 2 In vitro Study of the Effect of -Gallium upon LYmphoid Cells Materials and Method Rats. Thirty-eight male Lewis rats (135-195 g) were purchased from Charles River La~oratories (Portage, MI) for use in this experiment.
Esta~lish~ent of a Purified pro~ein deriY~tiye L~EAT!
specifiç T l~mPhocvte line. A specific PEAT-reactive T-cell line was prepared by conventional techniques. Cells (8xlO6/ml) from lymph nodes of CFA-immuni2ed Lewi~ rats were incubated for 3 days in tissue culture Petri dishes in RP~I
1640 (Whittaker M.A. Bioproducts, Walkersville, MD) containing 50 Utml penicillin, 50 ~g/ml streptomycin, 50 ~
2-mercaptoethanol, 2 mM gluta~ine, 26 mM ~epes~ 1~ fresh autologous rat serum, and 40 ~g/ml PEAT. Lymphobla&ts were obtained by centrifugation, using lymphocyte-separat~ng medium (Organo~ Teknika, Durha~, NC) (240 g, 25 min~, and the cells were washed and cultured in medium containing 10%
fetal bovine serum (Whittaker M.A. Bioproducts) and 10%
~/v) rat T-cell growth factor (24-hr super~atant from rat splee~ CellB stimulated with Concanav~lin A). After 4-8 days in culture, the cells were restimulated ~or 3 day~ wit~ -PEAT (20 ~g/~l) in the presence o~ ~ynerglc ~-~rradiated .

-8- PCT/USgl/068~2 (3300 r) thymocytes (107tml) as a ~ource of antigen presenting cells. The T-line cells werQ alternately expanded in rat growth factor or restimulated with antigen and irradiated thymocytes. After the ~econd round o~
antigen restimulation, ~n vitro lymphocyte prollferative assays revealed a PEAT-specific response. After establishment of the T-cell line, restimulation with antigen was performed at approximately two-week interval~.
Procedurç
To measure the effect of Ga on the PEAT-specific T-cell line, a lymphocyte proliferative assay was used with [3H]thymidine incorporation as the endpoint. T cells (2xlO4/well) were cultured in 150 ~l of RPMI complete medium together with 10~/well) were cultured in 150 ~l of RPMI
complete medium together with 106 irradiated (3300 r) thymocyte~ and 20 ~g/ml PD or 2 ~g/ml Concanavalin A in 96-- well round-bottomed plates (Flow, Maclean, VA). Cultures were incubated for a total of 72 hr in 7% CO2 at 37C in a humidified atmosphere and pulsed with [~]thymidine (1 l~Ci/well) (Amersham, Arlington Heights, IL) during the final 18 hr of culture. Cells were harvested using a semi-automatic sample harvester (Skatron, Sterling, YA) and counted by liquid ~cintillation. Cultures contained either no Ga or Ga nitrate at 1.0 mg/ml. In order to control for nonspecific toxicity of the Ga preparation, an aliquot of T
cell~ wa~ incubated with Ga (1.0 mg/ml) for 1 hr and washed prior to culture.
R~sults Figure 2 ~hows the effects of addition of gallium to PEAT-~pec~fic ~ line cell~ during stimulation with PEAT or Concanavalin A and a~tigen-presenting cells.
~a~Ple 3 Ex~ession of Maior Histocompatibility ÇQmplex Clas~ II Glycop~o~eins.
Sixty-four male BALB/c mice received an i.p. ln~Pction of 2 ml o~ 3~ thiogly olate medium in ~terile water to '.

W092/04896 -9~ PCT/U~91/06~02 ~nduce migration of macrophage~ to the peritoneum. A~ter 3-5 day6, the mice were euthanized and 15-20 x 1o6 cell~
coll~cted from the peritoneum of e~ch by lavage with ~ank~' balanced ~alt ~olution (Wh:Lttaker M.A. Bioproduct~).
Viability, determlned by trypan blue ~xclu6ion, wa~ always greater than 95~. The cell~ were added to Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum (Hyclone Laboratories, Lcgan, UT), 2 mM glutamine, 100 U of penicillin, and lOO ~g of 6treptomycin, to a final concentration of 2 x 105 cells/ml for each mouse. One-half milliliter of each cell suspension was added to chambers of multichambered Lab-Tek slides (Nunc, Inc., Naperville, IL).
Macrophages were allowed to adhere to the slides for 24 hr;
then nonadherent cells were removed by washing with Hanks' balanced salt solution. The macrophages were incubated for 48 hr with lOO U/well of murine recombinant ~-interferon (Amgen, Thousand Oaks, CA). A macrophage-activating factor, :
~-interferon stimulates the expression of I-~ (an MHC clas~
II glycoprotein) and enhances the cell'~ ability to kill microorganisms and tumor cell~. Gallium nitrate (0 ~A), 05 (B), 1.0 (C), or 2.5 mg (D)) was subsequently added to each well, and the percentage of cells expressing I-A was determined at 1, 4, 8, and 16 hr by indirect fluorescence, using a UV microscope (Zeiss, Oberkochen, W. Germany~
Specifically, the macrophages were treated with 5% rabbit ~erum at 4C to block Fc receptor binding. After 30 ~inutes the cell6 wero washed and then incubated with 0.5 ~g of monoclonal anti I-Ad (MKD-6, American Type Cultura Collection, Rockville, MD), grown in the same medium as ~he macrophages. MXD-6 i9 a cell line which produce~ cytotoxlc monoclonal antibodies which react with murine I-Ad antigen.
After 40 ~in 'at 4C) he ~ell~ ~ere washed with ~ank~', and FITC-conjugated goat anti~ouse F(ab' )2 immunoglobulin (Organon Teknika) was added for 40 minO This wa~
su~sequently washed off, the tops of the slides removed, a W092/04896 ~ 1 - o- PCT/US91/06802 coverslip placed over ~he cells, and the number of fluorescent cells assessed ln a blinded fashion.
Rç~lts Figure 3 ~hows a decline in the expresslon of I-A when peritoneal macrophages of BALB/c mice were incubated with gallium. This lnhibition of expression diminished with time, ranging from approximately 45S at 1 hr to 0~ (full recovery) by 16 hr. Cells remained viable throughout the study.
Exam~le 4 Treatment of Pre-Diabetic Non-Obes Q (NOD) Mice with Gallium Nitrate Prevents Development of Diabetes.
Diabetogenesis in NOD/mice is an immune media~ed disease, with generation of auto-immune reactivity against pancreatic ~ cells requiring participation of macrophages and T lymphocytPs. In the specific pathogen-free NOD/LT
colony, untreated virgin females exhibited a 79~ diabetes incidence by eight months of age compared to a 45S incidence in virgin males. Diabetes in NOD mice can be circumvented by a variety of immunomodulatory procedures initiated shortly after weaning. These include immunosuppressive treatment6 impairing viability and/or function of either macrophages or T cells. In this Example, gallium nitrate ifi used to circumvent diabetes.
Materials and ~ethods NOD mice. 24 NOD/Lt female mice from litters born between 12-l-90 and 12-6-90 from Jackson Laboratories, Bar Harbour, Maine were randomly sorted into two group of twelve. Mice were caged threej~ide ln double penned plastic boxe~ with a natural ingredient diet (old Guilford 96 w) and Libitum.
Gallium Nitrate. A citrated solution of gallium nitrate per 500 mg/20 ml was obtained from Ben Venue - Laboratories, Bedford, Ohio. Lot No. 89/215 wa3 used in this experiment.

W~92/04896 ~ PC~/US91/06802 P~roçedures At BiX weeks of age, twelve female~ received an in~ection i.p. of 45 mg/kg body weight followed by once weekly injection~ i.p. of 45 mg/kg body weight. The controlled group of twelve females received an in~ection o~
vehicle (citrated sallne ~olution) at the same time~. Mice were weighed and checked for glycosuria using TES-tape diagnostic tapes supplied by Eli Lilly and Company at weekly interval~. A diagno~is of diabetes was made if the mice remained glycosuria for three consecutive weeks and lost weight. Diabetic mice were euthanized without further analysis. At the end of 20 weeks, weekly injections of gallium nitrate in vehicle were discontinued; the mice were aged at 30 weeXs to determine whether absence of disea e would persist without treatment.
~esul~S
NOD/LT females after 14 weeks of gallium injections did not show reduced body weights compared to vehicle control~
(mean + SEM = 23.0 ~ O.7 g (n - l0) for gallium recipient~
versus 23.0 + 0.5 (n = 8) for vehicle controls. Two female~
in the gallium treatment group had to be deleted from the experiment due to development of malocculsions and subsequent weight loss. Malocculsions are detected sporadically in the NOD/Lt colony and are not considered to ~e direct effects of the gallium treatment.
Figure 4 depicts the diabetes incidence in the mice.
The ability of gallium nitrate injections to circumvent development of clinical diabete6 is unequivocal. Thare ar~
no ca~e~ of overt diabete in the group during the periQd o~
weekly qallium administration. Further, there wa~ no "breakthrough" of diabetes within a 5 week period a~ter cessation of gallium injections. In distinctio~, ~ sh~rp increase in c1iabetes incidence occurred in vehicle controls during the ~ame period (21-25 week6).

WO92/04896 ~ 12- PCr/~'S91/0~80' Example 5 Trans~lan~a~i~n Q~ MQuse---Heart The heart of a DBA/2 from Harland mouse waR removed.
The abdomen of a C57/BL/6 mouse from Sprague Dawley, Indianapolls, IN. was opened and the a~dominal aorta displayed. The donor heart was transplanted by attaching the donor aorta to the recipient abdominal aorta and the donor pulmonary artery to the recipient vena cava. A single dose of 45 mg/kg of elemental gallium was administered subcutaneously after the surgical procedure was completed.
The transplanted heart remained viable for eleven days. A
controlled experiment in a mouse from the same strain and source using the foregoing procedure without the administration of gallium nitrate allowed the heart to remain viable for only five days.
As used herein, the term "patient" refers to a war~
blooded animal such as a mammal which i5 affected with a disease, such as an autoimmune disease, or is in danger of rejection of a transplanted tissue or organ. It i~
understood that human~ are included within the scope of the term "patient. n Based on standard clinical and laboratory tests and procedures, an attending diagnostician, a~ a person skilled in the art, can readily identify those patients who are in need of treatment with immunosuppre6sive agents.
According to the present invention, in order to obtain the beneficial effects of gallium in treating autoimmune diseases and resi~tance to transplantation, pharmacautically acceptable gallium containing co~pounds ~re ad~inistered to the patient i~ an amount sufficient to provide therapeu~ic ~ -level3 of gallium. Therapeutio level~ are obtained when gallium is present in a steadyi6tate concentration in blood.
Typically, the amount of elemental gallium administered is from about 0.05 to about 50 mg/per kg per day of ~ody weight. Preferably, this amount range~ fro~ about 0.05 tD
about .5 mg/per kg of body weight~

~092/Oq896 -13~
3 1 P~/l,'S91/06802 Galli~m containlng compound~, effective wlth this invention, may b~ any gallium containing compound~ ln non-nephrotoxic amount~ to lnhibit or treat autoimmune disea~e~, and re6i~tanc~ to transplantation, in patients 6uffering from the aforementioned condition~ by administering to a patlent a therapeutically effective amount of such a compound. Preferably, the compounds may be selected ~rom the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.
Gallium containing compounds are useful in formulations having a variety of routes of administration. The route(s) of administration useful in a particular application for the treatment of autoimmune diseases, immuno~uppression and resistance to transplantation is apparent to one 6killed in the art. Routes of administration include but no~ llmlted to topical, transdermal, parenteral, transbronchial and transalveolar.
Formulations of gallium contalning compounds 6uitable for topical application include, but are ~ot l:Lmited to, implants; ointments, creams, resin~ and gels. For~ulation~
suitable for transdermal application include, but are not limited to, suspensions, oils, creams and ointments applied directly or attached to a protective carrier such a~ a patch. Formulations suitable for parenteral administration include, but are not limited to, sterile solution6 for intravenous, intramuscular or ~ubcutaneous iniection.
Formulations suitable for transbronchial and tran6alveolar administration include, but are not li~ited to, various types of aerosol~ for inhalation. The above-mentioned formulations are meant to describe but not limit the ~ethod~
of admini~tering gallium containing compound~. The m~thod~
of making the various formulation~ are within the ability of one skilled i~ the art and need not be described in detail.
.
The terms and expressions which had been ~mployed are used as ter~s of description and not of llmitation, ~nd W~92/04896 ~ 14-~ ~ , PCT/US91/06802 thQre i5 no intention in the U8Q of such term~ and expr~slon~ o~ excluding any Qquiv~lents of the feature shown and described or portions thereof, it being recognized that variou~ modifications are possible within the scope o~ the inventlon.

Claims (31)

What is Claimed Is:

1. A method of treating macrophage mediated autoimmune diseases comprising administering an effective amount of pharmaceutically acceptable gallium-containing compound suitable to provide therapeutic levels of gallium to a patient in need thereof.

2. A method according to claim 1 wherein the autoimmune disease is selected from the group consisting of autoimmune diseases involving various body systems including central nervous, cardiopulmonary, gastrointestinal, dermatological, endocrine, renal, reproductive and the hepato-billary systems.

3. A method according to claim 1 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

4. A method according to claim 3 wherein the gallium containing compound is gallium nitrate.

5. The method according to claim 1 wherein the gallium-containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

6. The method according to claim 4 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.

7. A method of preventing transplantation rejection which comprises administering an effective amount of a pharmaceutically acceptable gallium containing compound suitable to provide therapeutic levels of gallium to a patient in need thereof.

8. A method according to claim 7 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium fluoride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

9. A method according to claim 7 wherein the gallium containing compound is gallium nitrate.

10. The method according to claim 7 wherein the gallium-containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

11. The method according to claim 7 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.

12. A method of treating diseases beneficially treated by administration of compounds having immunosuppressive activity in a patient in need thereof, which comprises administering to such patient an effective amount of a pharmaceutically acceptable gallium containing compound suitable to provide therapeutic levels of gallium.

13. A method according to claim 12 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

14. A method according to claim 12 wherein the gallium containing compound is gallium nitrate.

15. The method according to claim 12 wherein the gallium-containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

16. The method according to claim 13 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.

17. A method of suppressing T-cell proliferation comprising administering an effective amount of pharmaceutically acceptable gallium-containing compound suitable to provide therapeutic levels of gallium to a patient in need thereof.

18. A method according to claim 17 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

19. A method according to claim 18 wherein the gallium containing compound is gallium nitrate.

20. A method according to claim 17 wherein the gallium-containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

21. The method according to claim 19 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.

22. A method of treating multiple sclerosis comprising administering an effective amount of pharmaceutically acceptable gallium-containing compound suitable to provide therapeutic levels of gallium to a patient in need thereof.

23. A method according to claim 22 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

24. A method according to claim 22 wherein the gallium containing compound is gallium nitrate.

25. A method according to claim 22 wherein the gallium containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

26. The method according to claim 22 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.

27. A method of treating rheumatoid arthritis comprising administering an effective amount of a pharmaceutically acceptable gallium containing compound suitable to provide therapeutic levels of gallium to a patient in need thereof.

28. A method according to claim 27 wherein the gallium-containing compound is selected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium lactate, gallium tartrate, gallium oxalate, gallium oxide and hydrated gallium oxide.

29. A method according to claim 27 wherein the gallium containing compound is gallium nitrate.

30. A method according to claim 27 wherein the gallium-containing compound is administered via a route selected from the group consisting of topical, transdermal, parenteral, transbronchial and transalveolar.

31. The method according to claim 27 wherein the amount of elemental gallium administered is about .05 mg/kg to about 50 mg/kg of body weight.