Compositions and methods to inhibit stem cell and progenitor cell binding to lymphoid tissue and for regenerating germinal centers in lymphatic tissues

Abstract

The present invention relates to compositions and methods of inhibiting stem cell binding to organs and tissues, including the blocking of stem cell binding to germinal centers present in lymph tissue. Disclosed are compositions and methods for regenerating germinal centers in lymphatic tissue. Included in the compositions are adjuvants, agonists to CD40, CD28 and the IL-21 receptor, and antagonist to CD20.

What is claimed is: 
     
         1 . A method to inhibit stem cells binding to lymphoid tissue comprising:
 administering the stem cells in conjunction with a therapeutic agent that inhibits binding of the stem cells to said lymphoid tissue.   
     
     
         2 . The method of  claim 1  wherein the lymphoid tissue is comprised of spleen, Peyer's patches and lymph nodes. 
     
     
         3 . The method of  claim 1  wherein the therapeutic agent inhibits binding of the stem cells to germinal centers within the lymphoid tissue. 
     
     
         4 . The method of  claim 3  wherein the germinal centers are present in a lymph tissue selected from the group consisting of spleen, Peyer's patches and lymph node tissue. 
     
     
         5 . The method of  claim 3  wherein the germinal center is active. 
     
     
         6 . The method of  claim 1 , wherein the therapeutic agent is selected from the group consisting of:
 agents that interfere with the synthesis of purines, the anti-metabolites, radiation to the spleen, chemotherapeutic agents, immunosuppressants, glucocorticoids, anti-beta amyloid agents, anti-rhesus factor, anti-TNF agents, anti-eotaxins, anti-T cell receptor (TCR) agents, anti-interferons agents, anti-interferon alpha agents, anti-interferon beta agents, anti-interferon gamma agents, anti-TGF agents, anti-TGFalpha agents, anti-TGF beta agents, anti-Integrins agents, anti-alpha 4 agents, anti-Interleukin agents, anti-Interleukin 1 agents, anti-Interleukin 2 agents, anti-Interleukin 4 agents, anti-Interleukin 5 agents, anti-Interleukin 6 agents, anti-Interleukin 12 agents, anti-Interleukin 13 agents, anti-Interleukin 23 agents, anti-IgE agents, anti-Vascular Adhesion Protein (YAP) agents, anti-B7 agents, anti-Vascular Endothelial Growth Factor (VEGF) agents, anti-BAFF (BLyS) agents, anti-CTLA4 agents, anti-complement agents, anti-CD2 agents, anti-CD3 agents, anti-CD4 agents, anti-CD5 agents, anti-CD20 agents, anti-CD23 agents, anti-CD25a agents, anti-CD40 agents, anti-CD154(CD40L) agents, anti-CD62L agents, anti-CD80 agents, anti-CD147 agents, anti-LFA1 agents, anti-(CD11a) agents, anti-CD18 agents, inhibitors of purine synthesis, inhibitors of pyrimidine synthesis, anti-proliferative agents, anti-metabolite agents, anti-folate agents, and anti-mTOR agents.   
     
     
         7 . The method of  claim 1  wherein the therapeutic agents are selected from the group consisting of: azathioprine, mycophenolic acid, leflunomide, teriflunomide, methotrexate, tacrolimus, ciclosporin, pimecrolimus, abetimus, gusperimus, thalidomide, lenalidomide, anakinra, sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9, eculizumab, infliximab, adalimumab, certolizumab pegol, afelimomab, golimumab, mepolizumab, omalizumab, nerelimomab, faralimomab, elsilimomab, lebrikizumab, ustekinumab, muromonab-CD3, otelixizumab, teplizumab, visilizumab, clenoliximab, keliximab, zanolimumab, efalizumab, erlizumab, afutuzumab, ocrelizumab, pascolizumab, lumiliximab, teneliximab, toralizumab, aselizumab, galiximab, gavilimomab, ruplizumab, belimumab, ipilimumab, tremelimumab, bertilimumab, lerdelimumab, metelimumab, natalizumab, tocilizumab, odulimomab, basiliximab, daclizumab, inolimomab, zolimomab aritox, atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gantenerumab, gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, siplizumab, talizumab, telimomab aritox, vapaliximab, vepalimomab, abatacept, belatacept, etanercept, pegsunercept, aflibercept, alefacept, rilonacept, lymphotoxin alpha and beta inhibitors, dacetuzumab SGN-40, HCD-32. 
     
     
         8 . The method of  claim 1 , wherein the binding of stem cells to the lymphoid tissue is inhibited by administering a therapeutic agent that down-regulates or blocks a CD45 antigen. 
     
     
         9 . The method of  claim 1  wherein the therapeutic agent is radiation. 
     
     
         10 . The method of  claim 1  wherein the stem cells are either exogenous or endogenous stem cells. 
     
     
         11 . The method of  claim 1  wherein the therapeutic agent is a chemotherapeutic agent. 
     
     
         12 . The method of  claim 1  wherein the stem cells are administered to treat a disease selected from the group consisting of: hematological malignancies, leukemias, lymphomas, cancers, osteopetrosis, aplastic anemia and cytopenias, sickle cell disease and thalassemia, limbal stem cell deficiency, breast cancer, acute myocardial infarction, coronary artery disease, peripheral vascular disease, heart failure, type I diabetes mellitus, type 2 diabetes mellitus, stroke, spinal cord injury, neuroblastoma, multiple sclerosis, systemic sclerosis, lupus erythematosus, chronic wound healing, burns, fracture healing, cartilage repair, CNS tumors, osteoarthritis, renal failure, Parkinson's Disease, myelomas, diabetic foot, liver and biliary cirrhosis, dilated cardiomyopathy, anemia, retinitis pigmentosa, Crohn's Disease, diabetic neuropathy, mastocytosis, ovarian cancer, epilepsy, myasthenia gravis, autoimmune diseases, granulomatous disease, osteonecrosis, liver failure, PMD disease, lypodystrophy, demyelinating diseases, cartilage defects, retinal disease, lupus nephritis, Alzheimer's Disease, traumatic brain injury, sarcoma, myositis, hyperglycemia, macular degeneration, ulcerative colitis, and muscle degeneration. 
     
     
         13 . A method for inhibiting binding of stem cells to lymph tissues in an individual comprising inhibiting the formation of germinal centers present in lymph tissues or destroying or ablating germinal centers in lymph tissue. 
     
     
         14 . The method of  claim 13  wherein a therapeutic agent is administered to the individual that inhibits the formation of the germinal cells or promotes destruction or ablation of the germinal cells wherein the therapeutic agent is selected from the group consisting of agents that interfere with the synthesis of purines, anti-metabolites, radiation, immunosuppressants, glucocorticoids, anti-beta amyloid agents, anti-rhesus factor, anti-TNF agents, anti-eotaxins, anti-T cell receptor (TCR) agents, anti-interferons agents, anti-interferon alpha agents, anti-interferon beta agents, anti-interferon gamma agents, anti-TGF agents, anti-TGFalpha agents, anti-TGF beta agents. anti-Integrins agents, anti-alpha 4 agents, anti-Interleukin agents, anti-Interleukin 1 agents, anti-Interleukin 2 agents, anti-Interleukin 4 agents, anti-interleukin 5 agents, anti-interleukin 6 agents, anti-Interleukin 12 agents, anti-Interleukin 13 agents, anti-Interleukin 23 agents, anti-IgE agents, anti-Vascular Adhesion Protein (VAP) agents, anti-B7 agents, anti-Vascular Endothelial Growth Factor (VEGF) agents, anti-BAFF (BLyS) agents, anti-CTLA4 agents, anti-complement agents, anti-CD2 agents, anti-CD3 agents, anti-CD4 agents, anti-CD5 agents, anti-CD20 agents, anti-CD23 agents, anti-CD25a agents, anti-CD40 agents, anti-CD J 54 (CD40L) agents, anti-CD62L agents, anti-CD80 agents, anti-CD147 agents, anti-LFA1 agents, anti-(CD11a) agents, anti-CD18 agents, inhibitors of purine synthesis, inhibitors of pyrimidine synthesis, anti-proliferative agents, anti-metabolite agents, anti-folate agents, and anti-mTOR agents. 
     
     
         15 . The method of  claim 13  wherein the therapeutic agent is a chemotherapeutic agent. 
     
     
         16 . A method for regenerating germinal centers in lymphatic tissue, wherein said germinal centers have been damaged by a chemical agent, a biologic agent or by radiation comprising administering one or more agents that stimulates regeneration of the germinal centers.