We claim:
1. An unmodified graft for use in a method of treating one or more disease(s) treatable
by transplantation in a subject,
wherein said method comprises a first step of introducing into said subject a
modified graft, and a second step of introducing into said subject said unmodified
graft,
wherein said modified graft is a cell graft containing immune cells, wherein said
modification inhibits CD4.
2. A modified graft for use in a method of treating one or more disease(s) treatable by
transplantation,
wherein said method comprises a first step of introducing into said subject said
modified graft, and a second step of introducing into said subject an unmodified
graft,
wherein said modified graft is a cell graft containing immune cells, wherein said
modification inhibits CD4.
3. A CD4 antagonist, preferably an anti CD4 antibody, for use in a method of treating
one or more disease(s) treatable by transplantation;
wherein said method comprises a first step of introducing into said subject a
modified graft, and a second step of introducing into said subject an unmodified
graft,
wherein said modified graft is a cell graft containing immune cells, wherein said
modification inhibits CD4.
4. An unmodified graft, a modified graft and/or a CD4 antagonist, wherein said
antagonist preferably is an anti CD4 antibody, for use in
i) a chirurgical transplantation method,
ii) a method of inducing transplantation tolerance, wherein a modified graft is used
for inducing transplantation tolerance towards an unmodified graft,
iii) a method of transferring one or more cell suspension(s), particularly stem cell
containing cell suspension(s) from a donor to a subject,
iv) a method of transferring one or more tissue(s) from a donor to a subject,
v) a method of transferring one or more partial organ(s) from a donor to a subject,

vi) a method of transferring one or more organ(s) from a donor to a subject,
vii) a method of transferring hematopoietic system reconstituting cells from a donor
source into a subject, optionally followed by transferring one or more organ(s),
from said donor source into said subject,
or
viii) a method for enhancing immune reconstitution in a subject, optionally
followed by transferring one or more organ(s) into said subject;
wherein said method comprises a first step of introducing into said subject a
modified graft, and a second step of introducing into said subject an unmodified
graft,
wherein said modified graft is a cell graft containing immune cells, wherein said
modification inhibits CD4.
The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims,
wherein said first step is carried out from 30 min to 50 years, particularly from one
hour to two months before said second step.
or
wherein said first step is carried out at least one hour, particularly at least three
weeks before said second step.
The unmodified graft for use, modified graft for use, or CD4 antagonist for use of any of the preceding claims, wherein said modified graft comprises stem cells.
The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims,
wherein each of said grafts is selected from the group consisting of a cell
suspension, a tissue and an organ;
particularly
i) wherein said modified graft is a cell suspension and said graft is a cell
suspension,
or
ii) wherein said modified graft is a cell suspension and said graft is a tissue,
or
iii) wherein said modified graft is a cell suspension and said graft is an organ.
The unmodified graft for use, modified graft for use, or CD4 antagonist for use of any of the preceding claims, wherein said modified graft is a cell graft containing

immune cells that comprises a CD4 antagonist, particularly an anti CD4 antibody, particularly bound to CD4 epitopes thereof;
particularly wherein said modified graft
I) is obtainable by an in vitro method comprising the step a) incubating a cell
graft containing immune cells with a CD4 antagonist, particularly an anti CD4
antibody, and optionally comprising the step b) removing unbound antibody
from said graft,
and/or
II) is a cell graft containing immune cells that comprises a CD4 antagonist,
particularly an anti CD4 antibody, bound to from 40 % to 100 % of the CD4
epitopes thereof.
9. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
claim 8;
wherein said incubating in step a) of said in vitro method is carried out for from 1
minute to 7 days,
particularly wherein said incubating is carried out
i) for from 1 to 150 minutes, particularly for from 5 minutes to 150 minutes,
more particularly for from 10 minutes to 150 minutes, more particularly for
from 30 minutes to 150 minutes, more particularly for from 40 minutes to
120 minutes, more particularly for from 45 minutes to 90 minutes,
especially for from 50 minutes to 70 minutes;
or
ii) for from 150 minutes to 7 days, particularly for from 150 minutes to 5
days, more particularly from 150 minutes to 3 days, more particularly from
150 minutes to 1 day, especially for from 150 minutes to 8 hours;
and/or
wherein said incubating in step a) of said in vitro method is carried out with an
antibody amount of from 0.1 p,g/ml to 10 mg/ml.
10. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims, wherein said method
i) implies tolerance or partial tolerance within said unmodified graft against the
recipient's tissue;
and/or
ii) implies tolerance or partial tolerance within the recipient's tissue against said
unmodified graft;
and/or

iii) implies a reduced likelihood of developing any one of the group consisting of GvHD, donor graft rejection, and organ rejection, upon transplantation of the unmodified graft.
11. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims,
i) wherein said modified graft is selected from the group consisting of a cell
suspension containing T cells and monocytes/macrophages the cell suspension comprising bone marrow cells, non-adherent bone marrow cells, peripheral blood cells, and/or cord blood cells; a cell suspension comprising lymphocytes, monocytes and/or macrophages; a stem-cell-containing tissue; a stem-cell-containing organ; an immune cell containing tissue; and an immune cell containing organ;
and/or
ii) wherein said modified graft is a cell suspension and wherein said method comprises administration of an amount of from 2 x 106 cells to 2 x 1015 nucleated cells to said subject.
12. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims, wherein
A) the modified graft and the unmodified graft are from HLA-related donors;
particularly
i) wherein the said HLA-related donors comprise no more than a total of 50% of HLA mismatches, preferably not more than 40% HLA mismatches, preferably not more than 30% HLA mismatches, preferably not more than 20% HLA mismatches, preferably not more than 10% HLA mismatches, preferably no HLA mismatch;
and/or
ii) wherein said HLA-related donors are selected from the group consisting of tissue-type matched donors, related twins or are the same donor;
especially wherein both the modified graft and the unmodified graft are from the
same donor,
and/or
B) wherein said modified graft and the unmodified graft are HLA-related;

particularly wherein said HLA-related grafts comprise no more than a total of 50% of HLA mismatches, preferably not more than 40% HLA mismatches, preferably not more than 30% HLA mismatches, preferably not more than 20% HLA mismatches, preferably not more than 10% HLA mismatches, preferably no HLA mismatch.
13. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of any of claims 3 to 12, wherein said CD4 antagonist is an anti CD4 antibody;
particularly wherein said anti CD4 antibody
i) is selected from the group consisting of Maxl6H5, OKT4A, OKTcdr4a,
cMT-412, YHB.46, particularly wherein said anti CD4 antibody is
Maxl6H5; or
ii) is antibody 3 OF 16H5; or iii) is obtainable from a cell line deposited with accession number ECACC
88050502; or iv) is obtainable from a cell line MAX.16H5/30F16H5 deposited with the
DSMZ on December 2, 2011; or
v) is antibody 16H5.chimIgG4; or vi) is obtainable from a cell line CD4.16H5.chimIgG4 deposited with the
DSMZ on December 2, 2011; or
vii) is an antibody comprising the VH and the VK of antibody 16H5.chimIgG4; or viii) is an antibody comprising a VH and a VK of an antibody obtainable from a
cell line CD4.16H5.chimIgG4 deposited with the DSMZ on December 2,
2011; or ix) is an antibody comprising any combination of a VH selected from SEQ ID
NOs: 1-10 and of a VK selected from SEQ ID NOs: 11-20, particularly
wherein said combination is selected from VH1/VK1, VH2/VK2, VH4/VK2
and VH4/VK4, especially wherein said combination is VH2/VK2, or

x) is a mixture of antibodies selected from the antibodies according to i) to ix) above.
14. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims,
wherein, prior to introduction into said subject, said unmodified graft and/or modified graft is/are additionally incubated with soluble bioactive molecules, particularly with agents promoting immunosuppression, immunotolerance and/or formation of regulatory T cells,
especially with an agent selected from the group consisting of 11-2, TGF-P, rapamycin, retinoic acid, 4-IBB ligand, and anti CD28 antibodies; or any combination thereof.
15. The unmodified graft for use, modified graft for use, or CD4 antagonist for use of
any of the preceding claims,
A) wherein the modified graft is used
i) for achieving tolerance or partial tolerance within the modified graft against
the recipient's tissue;
and/or
ii) for achieving tolerance or partial tolerance within the recipient's tissue
against the modified graft;
and/or
iii) for reducing the likelihood of any one of the group consisting of GvHD,
donor graft rejection, and organ rejection, upon transplantation of said modified
graft,
and/or
B) wherein the modified graft is used
i) for achieving tolerance or partial tolerance within the unmodified graft against
the recipient's tissue;
and/or
ii) for achieving tolerance or partial tolerance within the recipient's tissue
against the unmodified graft;
and/or
iii) for reducing the likelihood of any one of the group consisting of GvHD,
donor graft rejection, and organ rejection, upon transplantation of said
unmodified graft.