antithymocyte therapy

[Guest guest]

Meaning antibodies against T-cells. These rapidly deplete T-cells in

blood and tissue in monkeys, except in the thymus (PMID: 11233911).

Therefore the results of antithymocyte treatment should be a good

index of whether a disease is T-cell-mediated, unless those cells

from the thymus get out and proliferate - they shouldnt do so very

rapidly as the half-life of antibody in human serum/humor is fairly

long (something like a couple weeks).

Some of these abstracts have been whittled down.

I include citations on a minor therapeutic variant, anti-CD4 globulin.

I havent looked at any effects coming from the dose or schedule of

administration. I also havent seen any papers examining whether

lymphocyte depletion in the diseased tissue itself occurs (except

PMID: 8546738 which I havent read) ... that would be a good thing to

look for.

==========

Cell Immunol. 1984

To assess the role of T cells in collagen arthritis, a heterologous T

cell-specific antiserum (ATS) was administered intraperitoneally to

female Wistar-Furth rats. ATS treatment on Day -1, 1, 3, and 5 and

immunization with native chick type II collagen on Day 0 resulted in

a decreased incidence of arthritis (5 of 19, 26%) compared to

immunized rats given either nonimmune heterologous serum on these

days (20 of 25, 80%) or ATS injected on Day 5, 7, 9, and 11 (17 of

20, 85%) (P less than 0.001 for both comparisons). The early-ATS

protocol also was associated with a delayed onset and reduced disease

severity in the few rats in this group that did develop arthritis.

Both delayed-type hypersensitivity (DTH) and serum IgG antibody

titers to native type II collagen, measured on Day 10, were decreased

significantly (P less than 0.002) in rats administered ATS beginning

on Day -1 compared to the other two groups. These data suggest that T

cells contribute to the inception of collagen arthritis and that

their critical function occurs within the first 5 days after

immunization.

PMID: 6610483 [PubMed - indexed for MEDLINE]

============

Arthritis Rheum. 1996

OBJECTIVE. Between June 1, 1992 and August 31, 1994 we conducted an

open pilot study of antithymocyte globulin (ATGAM; Upjohn, Kalamazoo,

MI) in 10 patients with early systemic sclerosis (SSc). CONCLUSION.

At the dosage administered in this study, ATGAM appears ineffective

in improving the skin and pulmonary features of SSc.

PMID: 8670321 [PubMed - indexed for MEDLINE]

===========

Arthritis Rheum. 1989 Nov;32(11):1495-6. Related Articles, Links

Prolonged improvement in refractory rheumatoid arthritis after

antithymocyte globulin therapy of brief duration.

Shmerling RH, Trentham DE.

Publication Types:

Letter

PMID: 2818668 [PubMed - indexed for MEDLINE]

=================

Treatment of refractory Wegener's granulomatosis with antithymocyte

globulin (ATG): An open study in 15 patients.

CLINICAL NEPHROLOGY - EPIDEMIOLOGY - CLINICAL TRIALS

Kidney International. 65(4):1440-1448, April 2004.

SCHMITT, WILHELM H.; HAGEN, E. CHRISTIAAN; NEUMANN, IRMGARD; NOWACK,

RAINER; FLORES-SUAREZ, LUIS FELIPE 1; VAN DER WOUDE, FOKKO J.; FOR

THE EUROPEAN VASCULITIS STUDY GROUP

Abstract:

Background: A subset of patients with Wegener's granulomatosis does

not respond sufficiently to cyclophosphamide and glucocorticosteroids

or suffers of intolerable side effects. Anecdotal data suggest that

antithymocyte globulin (ATG) may be a treatment option for these

patients. We now describe 15 patients treated with ATG for refractory

Wegener's granulomatosis.

Methods: Fifteen patients with histologically proven active

refractory Wegener's granulomatosis (seven unresponsive to

cyclophosphamide, eight intolerant) were treated with ATG by a

protocol (SOLUTION protocol) designed by the European Vasculitis

Study (EUVAS) Group.

Results: Before ATG administration, patients had received a mean of

5.2 (range 2 to 7) different therapeutic approaches including

glucocorticosteroids and cyclophosphamide in all and experimental

therapies in six, without control of disease activity [2.8 (range 1

to 7) relapses during a disease duration of 63.2 (range 18 to 180)

months]. Thirteen of 15 patients showed a favorable response to ATG

with partial (N = 9) or complete (N = 4) remission. During a follow-

up of 21.8 (range 6 to 68) months, seven patients relapsed after a

mean of 8.4 (range 2 to 24) months (five minor and two major

relapses). Six patients are free of relapse for 22.3 (range 7 to 64)

months. Two patients died, 1 and 3 days following the first dose of

ATG, due to pulmonary hemorrhage and infection (one each). Although

further immunosuppressive treatment was required in all surviving

patients, a less intensive regimen could be applied in 12. Beside

fever and chills associated with the first gift of ATG, ATG was well

tolerated, with infections being observed in five cases and serum

sickness in two.

Conclusion: Anti-T-cell-directed treatment with ATG may be a

therapeutic option for severe refractory Wegener's granulomatosis if

simultaneous infections and fluid overload have been ruled out. In

patients with alveolar hemorrhage, ATG should only be used under

special caution.

=========

Neurology. 1997 Aug;49(2):351-7. Related Articles, Links

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody

cM-T412: results of a randomized, double-blind, placebo-controlled,

MR-monitored phase II trial.

van Oosten BW, Lai M, Hodgkinson S, Barkhof F, DH, Moseley IF,

AJ, Rudge P, McDougall A, McLeod JG, Ader HJ, Polman CH.

Department of Neurology, Free University Hospital, Amsterdam, The

Netherlands.

We report the results of a randomized, double-blind, placebo-

controlled exploratory trial of the chimeric monoclonal anti-CD4

antibody cM-T412 in 71 patients suffering from active relapsing-

remitting and secondary progressive multiple sclerosis. Infusion of

the antibody produced frequent but usually minor side effects and

resulted in a long-lasting reduction of circulating CD4-positive T

cells. There was no significant effect on the primary measure of

efficacy, the number of active lesions on monthly gadolinium-enhanced

MRI over 9 months. Further statistical evaluation provided evidence

that the degree of depletion of CD4-positive cells was important with

regard to treatment efficacy; using CD4 counts as a covariate there

was a statistically significant effect on the number of active

lesions over 18 months (p = 0.04). There was a statistically

significant reduction of 41% in the number of clinical relapses (a

secondary efficacy parameter) after 9 months (p = 0.02), which was

still present after 18 months, but this finding may be partly due to

physician unblinding. Other secondary efficacy parameters (Expanded

Disability Status Scale progression, number of courses of

methylprednisolone) were not influenced by anti-CD4 treatment. We

conclude that intravenous treatment with the monoclonal antibody cM-

T412 in the dosage we used results in a substantial and sustained

reduction of the number of circulating CD4-positive cells, but is not

able to reduce MS activity as measured by monthly gadolinium-enhanced

MRI, and is therefore unlikely to have a beneficial effect on the

clinical disease course. We found preliminary evidence suggesting

that more aggressive depletion of CD4-positive cells might lead to a

more substantial reduction in MRI activity.

Publication Types:

Clinical Trial

Clinical Trial, Phase II

Randomized Controlled Trial

PMID: 9270561 [PubMed - indexed for MEDLINE]

=============

Arthritis Rheum. 1996 Jan;39(1):52-6. Related Articles, Links

Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the

rheumatoid joint is associated with clinical improvement.

Implications for the development of immunotherapeutic dosing regimens.

Choy EH, Pitzalis C, Cauli A, Bijl JA, Schantz A, Woody J, Kingsley

GH, Panayi GS.

Guy's Hospital, UMDS, London, England.

OBJECTIVE. We assessed the effect of a daily dosing schedule of the

chimeric anti-CD4 monoclonal antibody (MAb), cM-T412, in rheumatoid

arthritis (RA) patients, and compared lymphocyte changes in the

peripheral blood (PB) and synovial fluid (SF) of these patients.

METHODS. Twelve patients received 50 mg/day of cM-T412 for 5 days,

followed by a maintenance treatment of 50 mg/week for 5 weeks (6

patients), or a retreatment course of 50 mg/day for 5 days after 5

weeks (6 patients). Paired PB and SF samples were obtained during

treatment for analysis. RESULTS. Changes in lymphocyte count and

coating with the MAb in PB did not reflect changes in the SF. After 5

daily treatments, the percentage of cM-T412-coated CD4+ lymphocytes

in SF correlated with the degree of clinical improvement seen in

patients at 2 weeks after the initiation of therapy (r = 0.75, P <

0.05). CONCLUSION. These results demonstrate the importance of

antibody dosage and treatment regimen in determining clinical

benefit. Our findings suggest that the percentage of cM-T412-coated

CD4+ lymphocytes in SF may be a predictor of clinical outcome.

Publication Types:

Clinical Trial

Randomized Controlled Trial

PMID: 8546738 [PubMed - indexed for MEDLINE]

=================

Arthritis Rheum. 1995 Aug;38(8):1097-106. Related Articles, Links

A randomized, double-blind, placebo-controlled study of CD4

monoclonal antibody therapy in early rheumatoid arthritis.

van der Lubbe PA, Dijkmans BA, Markusse HM, Nassander U, Breedveld FC.

University Hospital, Department of Rheumatology, Leiden, The

Netherlands.

OBJECTIVE. To assess the efficacy of the CD4 monoclonal antibody

(MAb) cM-T412 in the treatment of early rheumatoid arthritis (RA).

METHODS. Sixty patients were enrolled in a 6-week randomized, double-

blind, placebo-controlled study investigating multiple dose regimens

of cM-T412. Thirty patients subsequently were enrolled in a 9-month

randomized, double-blind, placebo-controlled study investigating

monthly single-dose administrations of cM-T412. RESULTS. Analysis of

clinical parameters revealed no changes in arthritis activity in the

groups that received CD4 MAb or the placebo group, and no difference

between the groups, in either in the first or the second part of the

study. The number of circulating CD4+ cells decreased substantially

in the patients treated with CD4 MAb. CONCLUSION. CD4 MAb treatment

of patients with early RA induced no therapeutic effect.

Publication Types:

Clinical Trial

Randomized Controlled Trial

PMID: 7639806 [PubMed - indexed for MEDLINE]

=================

J Rheumatol. 1998 Aug;25(8):1457-61. Related Articles, Links

A randomized, double blind, placebo controlled multicenter trial of

murine anti-CD4 monoclonal antibody therapy in rheumatoid arthritis.

Wendling D, Racadot E, Wijdenes J, Sibilia J, Flipo RM, Cantagrel A,

Miossec P, Eschard JP, Macro M, Bertin P, Liote F, Debiais F, Juvin

R, Le Goff P, Masson C.

Service de Rhumatologie, CHU Besancon, France.

OBJECTIVE: To assess safety and efficacy of a murine anti-CD4

monoclonal antibody (Mab) in a population of patients with rheumatoid

arthritis (RA) compared to treatment with placebo. METHODS: Fifty-

eight patients with defined RA were included in this placebo

controlled, randomized, double blind, multicenter study. Of the 48

women and 10 men (mean age 54.5 years), 25 were functional class II

and 31 were class III, with 9 years' disease duration; the mean of

previous disease modifying antirheumatic drugs was 4; 49 were taking

steroids (mean dosage 11 mg/day of prednisone). Eighty percent were

rheumatoid factor positive. All were in an active state of the

disease with: pain > 4 (mean at inclusion 6.6), tender joints > 4

(mean 12), swollen joint count > 3 (mean 9), morning stiffness > 45

min (mean 185), erythrocyte sedimentation rate > 30 mm (mean 59) or C-

reactive protein (CRP) > 30 mg/l (mean 63). Treatment was randomized

between murine anti-CD4 Mab (B-F5, Diaclone, 20 mg/day) or placebo

intravenously for 10 consecutive days. Efficacy was assessed with a

composite index (us), with evaluation of number of patients with

20 or 50% improvement in each group. Changes in measures of single

clinical or biological variables were also evaluated. RESULTS: The 2

groups were comparable at inclusion. Treatment was well tolerated.

Mild side effects (chills, fever, rash) were seen in both groups.

Percentage of patients with global 20 or 50% response did not differ

between placebo and Mab groups at Day 10 or at Day 30. Evaluation of

single variables showed reduced CRP, swollen joint count, and Ritchie

index in some B-F5 patients at Day 10, although in the B-F5 group as

a whole only CRP was significant. CONCLUSION: No significant

improvement in RA after murine anti-CD4 Mab was observed.

Publication Types:

Clinical Trial

Multicenter Study

Randomized Controlled Trial

PMID: 9712083 [PubMed - indexed for MEDLINE]