6 - azauridine , and particularly its &# 34 ; orally effective &# 34 ; triacetate derivative , azaribine , has been found useful suppressing the immune system and thereby suppressing the rejection reaction using a heart transplant model . 6 - azauridine is thought to exert its biological activity by inhibiting orotidine - 5 &# 39 ;- phosphate decarboxylase , thereby reducing the availability of uridine and cytidine . since uridine and cytidine are essential components for the synthesis of nucleic acids , their absence leads to an inability of immune lymphoid cells to proliferate and grow in response to the allograft . therefore treatment with 6 - azauridine or azaribine commenced prior to or immediately following transplant surgery will suppress the immune response that leads to tissue rejection . 6 - azauridine has been found to be a relatively safe drug compared to other cytotoxic agents . doses up to 1 , 000 mg / kg / day have been administered to patients for up to 10 days with only transient side effects , which disappeared promptly on discontinuing drug therapy . in one study , no side effects were observed at doses of 600 mg / kg / day for 10 days [ weiss et al . cancer chemotherap . repts . 53 , 79 - 82 ( 1969 )]. in another study , therapy at 400 mg / kg / day of azaribine has been employed for treating psoriasis and psoriatic arthritis [ levene et al ., arth . rheum . 19 , 21 - 28 ( 1976 )]. the principal side effect , namely anemia , was ameliorated by reducing or discontinuing therapy . no side effects such as renal , cardiac or liver damage , which are common with other immunosuppressants , have been observed with azaribine . the present invention is directed to the use of azaribine to suppress ongoing tissue rejection . the term azaribine as used herein refers to 2 &# 39 ;, 3 &# 39 ;, 5 &# 39 ;- triacetyl - 6 - azauridine , also called 6 - azauridine triacetate . this compound is metabolized to 6 - azauridine in vivo . in the method of the present invention , 6 - azauridine or azaribine is administered after the initiation of the rejection reaction to suppress the rejection of a transplanted organ or tissue . preferably azaribine is administered orally at a dosage of about 35 to about 600 milligrams per kilogram of body weight , per day . alternatively , parenteral administration of 6 - azauridine at a dosage of about 25 to about 500 milligrams per kilogram of body weight , per day may be used . in the practice of the present invention , in the event that an ineffective agent has been earlier employed , 6 - azauridine can be administered after initiation of the rejection reaction is observed . in cases where the patient is unable to tolerate oral medication , intravenous injection of 6 - azauridine is preferred . the method according to the present invention includes an initial waiting period between transplantation of the allograft and administration of the immunosuppressing compound to determine if administration of the immunosuppressing compound is in fact required . this waiting period is typically between 2 and 4 days , but not more than 6 days . general transplantation techniques for the kidney , the heart , the liver , skin and other organs and tissues are well known by those skilled in the art . in the examples given below , heterotrophic heart transplants were performed in mice . the heterotrophic heart transplant model has been used for more than twenty years as a model for the effectiveness of immunosuppressive drugs in humans . milom et al ., arch path 21 , 281 - 287 ( 1971 ), bahany et al ., j . pharm & amp ; exp . therap . 244 , 259 - 262 ( 1988 ), morris et al ., transplant proc . 21 1042 - 1044 ( 1989 ), morris et al ., transplant proc . 22 1059 - 1652 ( 1990 ), yuh et al ., transplantation 55 578 - 591 ( 1993 ). human clinical trial cannot be performed until the effectiveness of a drug has been demonstrated in an established animal model . one of the reasons for this is to establish that the drug is not toxic . in the case of 6 - azauridine , the drug has been used extensively for other conditions and treatments . the drug has been established as non toxic in humans even at very high doses , up to 1 , 000 mg / kg / day , slavick et al ., pharm . clinica 2 120 - 125 ( 1970 ), levine et al ., arthritis & amp ; rheumatation , 14 21 - 28 ( 1976 ), weiss et al ., cancer chemo . reports 53 79 - 82 ( 1969 ). mice are used as a model in immunology since their histocompatible genes are understood to a greater extent than any other mammal . a heterotrophic transplant than other mammals is used in these studies since there is no possibility that the transplanted tissue is compatible with the host . if the transplanted tissue were from an animal of the same strain the effectiveness of the immunosuppressant drug , would be inconclusive since the tissue transplanted could have been compatible with the host rather than the immunosuppressive drug being effective . to have a conclusive determination of the effectiveness of a drug heterotrophic transplants must be used . such experiments cannot be performed in humans as such experimentation is unethical and prohibited by governmental regulations . the procedure accepted by those skilled in the art to test the effectiveness of a drug for human use , is to test the drug in an established animal model . established animal models are considered to be predictive of the effects of drugs in humans . in the present invention it is preferred that oral administration of azaribine is used . it is further preferred that the azaribine be administered in a formulation which is resistant to absorption by the stomach . a preferred chemical formulation comprises a generally solid composition containing azaribine which is then encapsulated in an enteric coating as disclosed in u . s . pat . no . 5 , 023 , 083 , which is incorporated herein by reference . the formulation may be orally administered in tablet , capsule , suspension or other suitable form . it is understood that other methods of administrations such as oral administration of non - enteric coated azaribine or intravenous administration of 6 - azauridine , may be used as desired . in the practice of the present invention , it is desirable that administration of the azaribine or its equivalent is initially at a high dosage , i . e . about 600 milligrams per kilogram of body weight , per day for azaribine and about 500 milligrams per kilogram of body weight , per day for 6 - azauridine , to maximize suppression of the rejection reaction . however , undesirable side effects may develop at high doses of azaribine or 6 - azauridine . if side effects develop the dosage is reduced to a level where the side effects are reduced or eliminated . the effectiveness of the treatment of rejection of a transplanted tissue or organ with azaribine , at a time after the rejection reaction has been initiated , allows a reduction in the amount of drug which is to be administered . in addition the treatment does not have to be initiated as a preventative measure , instead , treatment can be withheld until needed , i . e . if the initial treament fails . thus the treatment may be initiated when other medications have been tried and found to be ineffective . with some conventional treatments , if the treatments are not initiated prior to the onset of the rejection reaction they will not be effective . since it is believed that azaribine acts to inhibit nucleic acid synthesis , it is unexpected that azaribine would be effective in suppressing the ongoing rejection reaction , i . e . after the rejection reaction has been initiated . after the rejection reaction has begun the t - cell population would have already undergone cell proliferation and growth . therefore , nucleic acid synthesis would no longer be essential for the rejection reaction to proceed and presumably would no longer be affected by nucleic acid synthesis . the rejection reaction would presumably be unaffected by a nucleic acid synthesis inhibitor . an experimental model system has been developed which correlates the immunosuppressive activity of a drug in the mammal ( mouse ) with its anticipated activity in human organ transplants [ babany , et al ., j . pharmacol . exp . therap . 244 , 259 - 262 ( 1988 )]. such correlations exist with respect to cyclosporin , fk 506 [ morris , et al ., transplant . proc . 2 1042 - 1044 ( 1989 )], mycophenolic acid [ morris et al ., transplant . proc . 22 , 1659 - 1662 ( 1990 )] and 15 - deoxyspergualin [ yuh et al ., transplant . 55 , 578 - 591 ( 1993 ); amemiya , ann . ny acad sciences 685 , 196 - 202 ( 1993 )]. the procedure is as follows : following implantation of neonatal hearts , derived from unsexed newborn balb / c mice , 24 - 48 hr . old into subcutaneous pouches prepared in the pinna of the ears of the recipients , male c3h / km mice 5 - 10 weeks old , heart grafts are examined for contractions every other day from day 4 to the final day of the experiment after surgery . in such transplantation procedures , the transplanted heart quickly becomes vascularized and begins to contract . about 4 days after transplantation , immune cells infiltrate the allograft and by day 6 infiltration is very advanced . milam et al . [ arch . path . 21 , 281 - 287 ( 1971 )] have shown that by day 8 untreated allografts are revascularized and infiltrated with polymorphonuclear leukocytes and by day 12 , the interstitial infiltration and myocardial necrosis is extensive . by day 14 no control hearts are contracting . the success rate of the immunosuppressive drug is expressed as the mean survival time in days after transplantation . in all groups , all hearts are contracting by day 6 . the length of graft survival time increases with increasing dosage of an effective immunosuppressive drug . the onset of rejection is marked by an increase in the body temperature of the recipient , infiltration of immune cells , inflammation , and in the case of the allografts described above the implanted heart ceases to contract . the onset of rejection is well known by those skilled in the art and such indicators are constantly monitored in transplant recipients . some of clinical manifestations of rejection include fever , graft swelling or tenderness , oliguria , and increases in bun and serum creatinine levels . any of these indicators can be monitored to indicate the onset of rejection . suppression of rejection is a reversal of these conditions after administration of the immunosuppressive drug . the procedure described above was carried out with 5 mice housed in a single cage . on the day after transplantation , azaribine was dissolved in their drinking water at a concentration of 0 . 5 mg / ml . the volume consumed by the mice was recorded daily . after 14 days the azaribine - containing water was replaced by water which contained no additions . the mice were then observed daily for rejection of the allografts . the results are summarized in table i . the procedure described in example 1 was repeated except the administration of 0 . 5 mg / ml azaribine , in drinking water , was commenced the second day after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except the administration of 0 . 5 mg / ml azaribine , in drinking water , was continued for 30 days after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except azaribine at a concentration of 0 . 75 mg / ml was administered in drinking water . the results are summarized in table i . the procedure described in example 1 was repeated except azaribine at a concentration of 1 mg / ml was administered in drinking water . the results are summarized in table i . the procedure described in example 1 was repeated except azaribine at a concentration of 1 mg / ml was administered in drinking water and the administration was continued for 23 days after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except azaribine at a concentration of 1 mg / ml was administered in drinking water and the administration was commenced four days after transplantation and was continued for 13 days after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except four mice were given azaribine at a concentration of 1 mg / ml of drinking water and the administration was commenced six days after transplantation and was continued for 13 days after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except four mice were given azaribine at a concentration of 2 mg / ml in drinking water and the administration was continued for 13 days after transplantation . the results are summarized in table i . the procedure described in example 1 was repeated except the administration of azaribine ( 1 mg / ml ) was combined with 0 . 08 mg / ml cyclosporin a and the administration was continued for 13 days . the results are summarized in table i . the procedure described in example 1 was repeated except the administration of azaribine ( 1 mg / ml ) was combined with 1 mg / ml mycophenolic acid and the administration was continued for 13 days . the results are summarized in table i . the results indicate that the administration of azaribine at a dosage of between about 97 mg / kg to about 320 mg / kg is effective in suppressing the rejection of an allograft , with the mean survival time being increased from about 10 to 12 days to about 18 days . the survival was increased even when treatment was not commenced until 4 or 6 days after transplantation . typically , rejection is already initiated by day 4 and is usually very advanced by day 6 . the delayed treatment had little or no effect on the mean survival time . the addition of cyclosporin or mycophenolic acid did not affect the mean rejection times . the above description of exemplary embodiments for the use of azaribine in immunosuppression are for illustrative purposes . variations which will be apparent to those skilled in the art , therefore , the present invention is not intended to be limited to the particular embodiments described above . also , the invention disclosed herein may be practiced in the absence of any element which is not specifically disclosed in the specification . the scope of the invention is defined by the following claims . table i__________________________________________________________________________exampledrug dose . sup . 1 schedule . sup . 2 ml / mouse . sup . 3 mg / mouse . sup . 4 mg / kg . sup . 5 mean . sup . 6 sem . sup . 7 n . sup . 8__________________________________________________________________________1 azaribine 0 . 5 1 - 14 5 . 8 2 . 9 103 . 0 17 . 3 0 . 7 52 azaribine 0 . 5 2 - 14 5 . 5 2 . 75 101 . 0 17 . 5 0 . 5 53 azaribine 0 . 5 1 - 30 5 . 3 2 . 63 97 . 0 18 . 5 0 . 5 54 azaribine 0 . 75 1 - 14 5 . 2 3 . 9 139 . 0 18 . 0 0 . 6 55 azaribine 1 1 - 14 4 . 2 4 . 2 147 . 0 18 . 4 0 . 7 56 azaribine 1 1 - 23 4 . 4 4 . 4 169 24 . 4 0 . 4 57 azaribine 1 4 - 13 5 5 188 . 0 15 . 6 0 . 4 58 azaribine 1 6 - 13 5 . 2 5 . 2 190 . 0 17 . 5 1 . 5 49 azaribine 2 1 - 13 4 8 320 19 . 0 2 . 3 410 aza . sup . 9 / csa . sup . 10 1 / 0 . 08 * 1 - 13 4 . 6 4 . 6 162 . 0 18 . 8 0 . 8 511 aza / myco . sup . 11 1 / 1 * 1 - 13 4 . 8 4 . 8 166 . 0 18 . 4 1 . 0 5__________________________________________________________________________ . sup . 1 mg / ml in drinking water . sup . 2 indicates the day , after transplantation , treatment was started - an ended . sup . 3 ml of drinking water consumed per mouse per day . sup . 4 mg of drug consumed per mouse per day . sup . 5 mg of drug consumed per kg of body weight per day . sup . 6 mean survival time of the allograft , in days , after transplantatio . sup . 7 standard error of the mean . sup . 8 number of mice per test . sup . 9 azaribine . sup . 10 cyclosporin a . sup . 11 mycophenolic acid . sup . 12 mg / ml
a method for suppressing the rejection of an allograft comprising administering azaribine at a time when the recipient of the allograft begins to mount a reject reaction against the allograft .