Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-03-03
2002-09-10
Chan, Christina Y. (Department: 1644)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S093700, C424S085200, C424S093710
Reexamination Certificate
active
06447765
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is generally related to pharmaceutical agents useful in treating graft-versus-host disease (GVHD) in patients that have received allogenic bone marrow transplants.
BACKGROUND OF THE INVENTION
Organ transplantation is now used with great success to improve the quality of human life. Substantial progress has been made in using kidneys, hearts, and livers from unrelated individuals. However, transplantation of hematopoietic stem cells from an unrelated (or allogeneic) donor is a more complicated endeavor. Here multipotent stem cells which have the capacity to regenerate all the blood-forming elements and the immune system are harvested from bone marrow or peripheral blood from one individual are transferred to another. However, histocompatibility differences between donor and recipient results in a higher incidence of transplant-related complications, and has limited the use of this procedure (Forman et al.,
Blackwell Scientific Publications
, 1994).
It is unfortunate that only few individuals are candidates for allogeneic hematopoietic stem cell transplantation at the present time because the spectrum of diseases treatable by this procedure has steadily increased. These diseases now include hematologic malignancies such as the acute or chronic leukemias, multiple myeloma, myelodysplastic syndromes; lymphomas; and the severe anemias such as aplastic anemia or thalassemia.
Allogeneic stem cell transplantation begins with treatment of the recipient with a highly immunosuppressive conditioning regimen. This is most commonly accomplished with high doses of chemotherapy and radiation which effectively kill all the blood forming elements of the bone marrow. Besides preparing the recipient bone marrow for donor stem cell transplantation, the conditioning regimen serves to kill much of the malignancy that remains in the body. The period of time between the completion of the conditioning regimen, and engraftment of the donor stem cells is the most dangerous for the recipient. It is during this time that the patient is completely immunocompromised and susceptible to a host of life-threatening infections. This vulnerability persists until the grafted donor stem cells proliferate and differentiate into the needed white blood cells and immune cells needed to combat infections.
Moreover, donor stem cell preparations generally contain immune cells called T lymphocytes. Unless the donor stem cells originate from an identical twin the transferred T cells turn against the recipient's tissues and trigger a deadly ailment called graft versus host disease (or GVHD). This is because the donor T lymphocytes recognize histocompatibility antigens of the recipient as foreign and respond by causing multi-organ dysfunction and destruction.
Current techniques of immunosuppression have made allogeneic stem cell transplantation from a related, histocompatible (HLA-matched) donor much safer than it once was. Allogeneic stem cell transplantation from an unrelated, HLA-matched donor is commonly complicated by serious, often fatal GVHD. The threat of GVHD is even higher when the stem cell donor is HLA mismatched.
Since only 30% of patients in need of allogeneic stem cells will have a sibling with identical histocompatibility antigens (Dupont, B.,
Immunol Reviews
157:12, 1997), there is a great need to make HLA-matched unrelated, and HLA-mismatched transplantation a safer procedure. There have been two principal approaches to resolving this problem. The first has been to deplete the graft of contaminating T lymphocytes and the second has been to inactivate the T cells so they cannot attack the recipient.
In the 1970's it became evident that ex-vivo removal of mature T lymphocytes from a bone marrow graft prior to transplantation dramatically decreased or prevented GVHD in animals receiving marrow grafts across major histocompatibility barriers (Rodt, H.
J. Immunol
4:25-29, 1974; and 4 Vallera et al.,
Transplantation
31:218-222, 1981). However, with T cell depletion the incidence of graft failure, graft rejection, relapse of leukemia, and viral-induced lympho-proliferative disease markedly increased (Martin et al.
Blood
66:664-672, 1985; 6 Patterson et al.
Br J Hematol
63:221-230, 1986; Goldman et al.
Ann Intem Med
108:806-814, 1988; and Lucas et al.
Blood
87:2594-2603, 1996). Thus, the transplantation of donor T cells on the stem cells has beneficial as well as deleterious effects. One needs the facilitating effect of the T cells on the engraftement of stem cells and the now well recognized graft-versus-tumor effects, but not graft-versus host disease.
Several approaches have been used to decrease T cell activation. These include: 1) in vivo immunosuppressive effects of drugs such as FK506 and rapamycin (Blazar et al.
J. Immunol
153:1836-1846, 1994; Dupont et al.
J. Immunol
144:251-258, 1990; Morris,
Ann NY Acad Sci
685:68-72. 1993; and Blazar et al.
J Immunol
151:5726-5741, 1993); 2) the in vivo targeting of GVHD-reactive T cells using intact and F(ab′)2 fragments of monoclonal antibodies(mAb)reactive against T cell determinants or mAb linked to toxins (Gratama et al.
Amj Kidney Dis
11:149-152, 1984; Hiruma et al.
Blood
79:3050-3058, 1992; Anasetti et al.
Transplantation
54:844-851, 1992; Martin et al.
Bone Marrow Transplant
3:437-444, 1989); 3) inhibition of T cell signaling via either IL-2/cytokine receptor interactions (Herve et al.
Blood
76:2639-2640, 1990) or the inhibition of T cell activation through blockade of co-stimulatory or adhesogenic signals (Boussiotis et al.
J Exp Med
178:1753-1763, 1993; Gribben et al.
Blood
97:4887-4893, 1996; and Blazar et al.
Immunol Rev
157:79-90, 1997); 4) the shifting of the balance between acute GVHD-inducing T helper-type 1 T cells to anti-inflammatory T helper-type 2 T cells via the cytokine milieu in which these cells are generated (Krenger et al.
Transplantation
58:1251-1257, 1994; Blazar et al.
Blood
88:247, 1996, abstract; Krenger et al.
J Immunol
153:585-593. 1995; Fowler et al.
Blood
84:3540-3549, 1994); 5) the regulation of alloreactive T cell activation by treatment with peptide analogs which affect either T cell receptor/major histocompatibility complex (MHC) interactions, class II MHC/CD4 interactions, or class I MHC/CD8 interactions (Townsend and Korngold (unpublished data)); and 6) the use of gene therapy to halt the attack of donated cells on the recipient's tissues (Bonini et al.
Science
276:1719-24, 1997).
There is suggestive evidence that the T lymphocytes from non-identical donors can become tolerant to the recipient's tissues. Unlike patients who receive solid organ allografts for whom life-long immunosuppressive therapy is needed to control chronic rejection, there is evidence of immunologic tolerance with stem cell allografts. The majority of these patients can be withdrawn from immune suppression without further evidence of GVHD (Storb et al.
Blood
80:560-561, 1992; and Sullivan et al.
Semin Hematol
28:250-259, 1992).
Immunologic tolerance is a specific state of non-responsiveness to an antigen. Immunologic tolerance generally involves more than the absence of an immune response; this state is an adaptive response of the immune system, one meeting the criteria of antigen specificity and memory that are the hallmarks of any immune response. Tolerance develops more easily in fetal and neonatal animals than in adults, suggesting that immature T and B cells are more susceptible to the induction of tolerance. Moreover, studies have suggested that T cells and B cells differ in their susceptibility to tolerance induction. Induction of tolerance, generally, can be by clonal deletion or clonal anergy. In clonal deletion, immature lymphocytes are eliminated during maturation. In clonal anergy, mature lymphocytes present in the peripheral lymphoid organs become functionally inactivated.
Following antigenic challenge stimulation, T cells generally are stimulated to either promote antibody production or cell-mediated immunity. However,
Chan Christina Y.
Dorsey & Whitney LLP
Haddad Maher
Kosslak Renee M.
Silva Robin M.
LandOfFree
Use of cytokines and mitogens to inhibit graft versus host... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of cytokines and mitogens to inhibit graft versus host..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of cytokines and mitogens to inhibit graft versus host... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2906768