Methods for identifying patients at risk for costimulation blockade resistant rejection

Abstract

The present invention provides methods utilizing changes in CD4+CD57+ T cells levels for determining the susceptibility of a transplant patient or patient in need thereof to costimulation blockade resistant rejection. These methods are useful for identifying effective drug regimens for the treatment of immune disorders associated with graft transplantation and/or maintenance of a transplant.

What is claimed is: 
     
         1 . A method of predicting if a transplant patent is at risk for costimulation blockade resistant rejection, the method comprising:
 (a) acquiring a blood sample from a person receiving costimulation blockade therapy;   (b) quantitating the amount of CD4+CD57+ T cells and   (c) comparing the percentage of CD4+CD57+ T cells in the test sample with the percentage of CD4+CD57+ T cells of a reference,   
       wherein the percentage of CD4+CD57+ T cells in the test sample is higher than the reference. 
     
     
         2 . A method of predicting if a patent is at risk for costimulation blockade resistant rejection, the method comprising:
 (a) acquiring a blood sample from a person in need of a transplant;   (b) quantitating the amount of CD4+CD57+ T cells and   (c) comparing the percentage of CD4+CD57+ T cells in the test sample with the percentage of CD4+CD57+ T cells of a reference, wherein the percentage of CD4+CD57+ T cells in the test sample is higher than the reference.   
     
     
         3 . The method according to  claim 1  or  2  wherein the percentage of CD4+CD57+ T cells is elevated at least 2 fold when compared to the percentage of CD4+CD57+ T cells in the reference. 
     
     
         4 . The method according to  claim 1  or  2  wherein the reference is blood from normal healthy controls or stable transplant patients; or a reference value determined from a representative number of normal healthy controls or stable transplant patients. 
     
     
         5 . The method according to  claim 1  or  2  wherein the costimulation blockade therapy is L104EA29YIg comprising:
 (a) an amino acid sequence beginning with methionine at position 27 and ending with lysine at position +357 or glycine at position +356 of  FIG. 4 , or 
 (b) an amino acid sequence beginning with alanine at position 26 and ending with lysine at position +357 or glycine at position +356 of  FIG. 4 . 
 
     
     
         6 . The method according to  claim 5  wherein the L104EA29YIg molecule administration regimen comprises an early phase regimen, wherein the early phase regimen may range from the first 3 to 6 months post-transplantation and involves administration that initially is more frequent than monthly. 
     
     
         7 . The method according to  claim 6  wherein the early phase administration regimen comprises administration of the L104EA29YIg molecule on day 1, week 2 visit, week 4 visit, week 8 visit and week 12 visit. 
     
     
         8 . The method according to  claim 7  wherein the early phase administration regimen comprises administration of L104EA29YIg molecule on day 5. 
     
     
         9 . The method according to  claim 7  wherein the early phase administration regimen comprises administration of L104EA29YIg molecule on week 6 visit, week 10 visit, month 4 visit, month 5 visit and month 6 visit. 
     
     
         10 . The method according to  claim 6  wherein the administration regimen further comprises a maintenance phase regimen wherein the maintenance phase regimen begins after the early phase regimen ends and wherein administration of L104EA29YIg molecule is not more frequent than monthly. 
     
     
         11 . The method according to  claim 6  wherein the effective dose of L104EA29YIg molecule during the early phase is about 10 mg/kg weight of the subject. 
     
     
         12 . The method according to  claim 10  wherein the effective dose of L104EA29YIg during the maintenance phase is about 5 mg/kg weight. 
     
     
         13 . The method according to  claim 5  wherein the effective dose of the L104EA29YIg molecule is about 10 mg/kg weight of the subject with an administration regimen comprising administration on days 1, 15, 29, 57, 85 and 5 gm/kg monthly thereafter. 
     
     
         14 . The method according to  claim 5  wherein the effective dose of the L104EA29YIg molecule is about 10 mg/kg weight of the subject with an administration regimen comprising administration on days 1, 5, 15, 29, 57, 85 and 5 mg/kg monthly thereafter. 
     
     
         15 . The method according to  claim 5  wherein the effective dose of the L104EA29YIg molecule is about 10 mg/kg weight of the subject with an administration regimen comprising administration on days 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, 169 and 5 mg/kg monthly thereafter. 
     
     
         16 . The method according to  claim 1  or  2  wherein the transplant rejection comprises solid organ, tissue and/or cell transplant rejection. 
     
     
         17 . The method according to  claim 16  wherein the transplant rejection comprises skin, islet cells, muscles, hepatocytes, neurons, heart, liver, kidney, lung, appendages, limbs, nose, ear or face transplant rejection. 
     
     
         18 . The method according to  claim 16  wherein the transplant rejection is kidney transplant rejection. 
     
     
         19 . The method according to  claim 1  or  2  wherein the costimulation blockade therapy is L104EA29YIg administered so to maintain a target trough serum concentration between about 3 μg/ml and about 30 μg/ml.