Thymoglobulin: Presence and Affect in the Central Lymphatic Compartment

This study proposes to examine the effect of TMG therapy upon the cellular elements within the central (bone marrow) and peripheral (lymph node) lymphoid compartments of humans. Briefly, bone marrow aspirates and lymph nodes will be obtained at the time of transplant, from renal transplant recipients receiving TMG induction therapy. For comparative purposes, peripheral blood samples will also be obtained. Lymphocytes from these compartments will be assessed for CD antigen expression, apoptosis, cytokine production following memory immune responses, and functional assays to assess potential regulatory T-cell (Treg) activity.

Study Overview

• Status: Completed
• Conditions: Immunosuppression; Renal Transplantation
• Intervention / Treatment: Drug: anti-thymocyte globulin; Drug: anti-thymocyte globulin; Drug: anti-thymocyte globulin

Detailed Description

Polyclonal anti-thymocyte globulins are used with increasing frequency to induce immunosuppression in organ transplant recipients. Induction therapy is used for the majority of persons receiving kidney transplant. In 2004, 72% of patients that received a kidney transplant also received induction therapy. This number is up from 46% reported in 1995. Anti-Thymocyte Globulin is the most commonly used agent for induction therapy. It was used for 37% of kidney recipients in 2004, and its use appears to be increasing year over year. A prominent example of this class of drugs is Thymoglobulin(TMG), a purified, pasteurized gamma immune globulin, which is obtained by immunization of rabbits with human thymocytes. The resulting preparation contains polyclonal antibodies directed against multiple T-cell markers, including CD antigens, HLA, and homing receptors.

Although the mechanism of action for the immunosuppressive effects of TMG has not been fully elucidated, there is evidence that complement-dependent cell lysis and depletion, cell-surface antigen modulation, blocking of adhesion molecules, and partial T-cell activation/anergy may play potential roles.

Many of the effects of TMG are evident in the peripheral blood compartment, including a rapid decline in circulating T-cells. Non-human primate studies have demonstrated that TMG treatment leads to depletion of T-cells via apoptosis in peripheral lymphoid tissues (spleen and lymph nodes), but no studies have been conducted to assess the effect of TMG in the bone marrow, and no studies have examined the peripheral lymphoid tissue in humans receiving TMG therapy.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All subjects age 18 years or older who qualify to receive a living (related or unrelated) kidney allograft using steroid free induction immunosuppression.
2. Single organ recipient (kidney only)
3. Subjects receiving first renal transplant
4. Women of childbearing potential should have a negative serum pregnancy test within 1 week prior to beginning study medications
5. Subjects with no prior history of immunosuppression
6. Subjects with no systemic illness (i.e. diabetes, autoimmune disease)
7. Subjects with negative serologies (Hep B, Hep C, HIV)
8. Subjects who are candidates for TMG induction
9. Subjects providing written consent
10. Subjects who are compliant and able to complete all the assessment procedures

Exclusion Criteria:

1. Subjects less than 18 years of age
2. Subjects who do not meet criteria for steroid free protocol
3. Subjects who are pregnant, lactating or nursing
4. Child bearing women not willing to use a reliable form of contraception
5. Subjects with a known allergy to rabbits or rabbit products
6. Subjects receiving other medications considered to be experimental

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group I; Administration of anti-thymocyte globulin post-operative days -6,-4,-2, and 0	Drug: anti-thymocyte globulin; Administration of anti-thymocyte globulin at post-operative days -6, -4, -2 and 0; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; anti-thymocyte globulin post-operative days -2, 0, 2 and 4; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; Post-operative days 0, 2, 4 and 6; Other Names: Thymoglobulin
Other: Group II; Administration of anti-thymoglobulin post-operative days -2, 0, 2 and 4	Drug: anti-thymocyte globulin; Administration of anti-thymocyte globulin at post-operative days -6, -4, -2 and 0; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; anti-thymocyte globulin post-operative days -2, 0, 2 and 4; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; Post-operative days 0, 2, 4 and 6; Other Names: Thymoglobulin
Other: Group III; Administration of anti-thymocyte globulin post-operative days 0, 2, 4 and 6	Drug: anti-thymocyte globulin; Administration of anti-thymocyte globulin at post-operative days -6, -4, -2 and 0; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; anti-thymocyte globulin post-operative days -2, 0, 2 and 4; Other Names: Thymoglobulin; Drug: anti-thymocyte globulin; Post-operative days 0, 2, 4 and 6; Other Names: Thymoglobulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary objectives of this pilot study are to examine lymphocyte marker expression, quantitate specific lymphocyte subsets and apoptosis, and assess immune function in subjects receiving TMG.	Pretransplant days -6, -4, -2, 0; Post-transplant days 2, 4, 6

Collaborators and Investigators

• Sponsor: Swedish Medical Center
• Collaborators: Genzyme, a Sanofi Company
• Investigators: Principal Investigator: William H Marks, MD PhD, Swedish Medical Center; Principal Investigator: Paul Warner, PhD, Bloodworks

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: July 9, 2008
• First Submitted That Met QC Criteria: July 11, 2008
• First Posted (Estimate): July 14, 2008

Study Record Updates

• Last Update Posted (Estimate): August 4, 2011
• Last Update Submitted That Met QC Criteria: August 2, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Immunosuppression; Thymoglobulin; Kidney Transplant; Induction therapy; Renal Transplant
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: TMG 617