T-Cell Disorders Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD more...
Exploration of mutations and analysis of cellular changes related to lymphocyte defects and immune dysregulation has fueled the development of novel treatment options for some primary T-cell disorders that might otherwise by fatal.
Sinopulmonary infections with common viral and bacterial agents are characteristic of partial T-cell disorders. Conventional therapy appropriate for the immunologically healthy host is administered, although patients with T-cell defects characteristically have more prolonged and severe clinical courses. Prophylaxis against infection by respiratory syncytial virus (RSV) using RSV-polyclonal immunoglobulin or the humanized monoclonal antibody, palivizumab, is specifically indicated in patients with T-cell disorders. Mucocutaneous candidiasis is more frequent but is conventionally treated in patients, and the disease uncommonly disseminates.
Bone marrow transplantation must be offered early in infancy to patients with Wiskott-Aldrich syndrome (WAS) to ensure better outcome. In addition, transplantation is the only effective treatment in most patients with Chediak-Higashi syndrome (CHS) and is indicated prior to development of the accelerated phase. Patients with DiGeorge syndrome (DGS) rarely have complete absence of T-cell function; these few patients require stem cell reconstitution, usually via bone marrow transplantation.
Routine childhood immunizations are usually indicated because patients with partial T-cell defects, even those with abnormalities in immunoglobulin levels, often respond with adequate specific antibody titers, although the levels may be lower than normal. However, administration of the oral live-attenuated poliovirus vaccine is contraindicated and should be replaced with the inactivated poliovirus vaccine. As a result of the frequency of bacterial sinopulmonary infections, administration of the conjugated pneumococcal vaccine (Prevnar) is particularly important.
Usually, treatment in persons with autoimmune disorders mirrors that for hosts who are immunocompetent. However, infectious complications pose a greater risk in patients with T-cell disorders who receive systemic steroids and other immunosuppressive drugs.
Overproduction of cytokines by T cells and other effector cells of the immune system can be controlled through use of anticytokine monoclonal antibodies, such as anti–tumor necrosis factor (TNF)–α (infliximab), for inflammatory bowel disease.
Insulin-dependent diabetes mellitus (IDDM), hypoadrenalism, hypothyroidism, glomerulonephritis, and autoimmune enteropathy present in patients at unusually young ages, typically in patients younger than 1 year who have immune dysregulation/autoimmunity disorders.
Patients with WAS and older patients who have chromosomal breakage syndromes (CBSs) have a high risk of malignancy. Chemotherapy in patients with ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) is not usually tolerated at conventional doses because of DNA instability. Thus, lower doses and longer intervals between doses are usually used.
Gene therapy is being studied as a possible alternative to allogeneic hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency (SCID), as well as a treatment for WAS.[18, 19]
Several drugs that block the lymphocyte voltage-gated potassium channel, kv1.3, as well as biologic therapies, are being explored as autoimmune disease treatments.[20, 21]
Mesenchymal stem cells have shown some promise in enhancing engraftment and both preventing and treating GVHD in bone marrow transplant recipients.
Antithymocyte globulin has been shown to reduce acute and chronic GVHD in randomized trials.
With the exception of cardiac procedures in patients with DGS, surgery is not usually required for patients with partial T-cell disorders.
Splenectomy has been used to control autoimmune hemolytic anemia and thrombocytopenia in patients with WAS and immune dysregulation/autoimmunity syndromes. In patients with WAS and Fas and Fas ligand deficiencies, overwhelming postsplenectomy sepsis has occurred despite immunization and antibiotic prophylaxis directed against Streptococcus pneumoniae.
Tumor-stage vulvar mycosis fungoides responded to local low-dose radiotherapy (Bakar et al, 2014).
Clinical immunologists and geneticists are integral to the evaluation and treatment in patients with partial T-cell disorders.
Intervention performed by neurologists is important in patients with CBSs and CHS.
Physical therapists and rehabilitation specialists are critical to achieving optimal functioning in patients with CBSs and CHS.
Autoimmune disorders are best controlled with the help of collaboration by hematologists, endocrinologists, and gastroenterologists.
The malignancies in CBSs may require alteration of chemotherapeutic regimens because of the increased DNA instability of host cells.
When a T-cell disorder is suspected, the Immune Deficiency Foundation offers a consultation service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital Boston), and New York City (The Jeffrey Modell Foundation) are funded to provide molecular analysis or can assist in contacting other research facilities.
As with other primary immunodeficiencies, supplemental nutrition can be an essential component of care for the patient with chronic enteropathy or chronic infection.
Unfortunately, many patients remain thin with short stature or become wasted.
The goal of care is to optimize daily functioning. Care to minimize exposure to certain viruses (eg, RSV, varicella) is important, but complete isolation is not recommended for patients with partial T-cell disorders.
Patients with WAS and CHS who have increased bleeding tendencies must be educated to avoid trauma and, especially, to wear helmets during certain activities.
Liston A, Enders A, Siggs OM. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat Rev Immunol. 2008 Jul. 8(7):545-58. [Medline].
Fernandes NF, Rozdeba PJ, Schwartz RA, Kihiczak G, Lambert WC. Pityriasis lichenoides et varioliformis acuta: a disease spectrum. Int J Dermatol. 2010 Mar. 49(3):257-61. [Medline].
Harrington L, Sokol L, Holdener S, Shao H, Zhang L. J Cutaneous Pathology Cutaneous Gamma-delta (?d) T-cell Lymphoma with Central Nervous System (CNS) Involvement: Report of a Rarity with Review of Literature. J Cutan Pathol. 2014 Oct 8. [Medline].
Foppoli M, Ferreri AJ. Gamma-delta t-cell lymphomas. Eur J Haematol. 2014 Aug 23. [Medline].
Martinez-Escala ME, Sidiropoulos M, Deonizio J, Gerami P, Kadin ME, Guitart J. ?d T cell-rich variants of pityriasis lichenoides and lymphomatoid papulosis: benign cutaneous disorders to be distinguished from aggressive cutaneous ?d T cell lymphomas. Br J Dermatol. 2014 Aug 21. [Medline].
McGeachy MJ. Th17 memory cells: live long and proliferate. J Leukoc Biol. 2013 Sep 4. [Medline].
Fischer A, Cavazzana-Calvo M, De Saint Basile G, DeVillartay JP, Di Santo JP, Hivroz C, et al. Naturally occurring primary deficiencies of the immune system. Annu Rev Immunol. 1997. 15:93-124. [Medline].
Holst J, Wang H, Eder KD, et al. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat Immunol. 2008 Jun. 9(6):658-66. [Medline].
Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc. 2009. 84(1):16-22. [Medline]. [Full Text].
McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011 Jan. 90(1):1-18. [Medline].
Korgavkar K, Xiong M, Weinstock M. Changing Incidence Trends of Cutaneous T-Cell Lymphoma. JAMA Dermatol. 2013 Sep 4. [Medline].
Chen Z, Ye W, Long Z, Ding D, Peng H, Hou X, et al. Targeted Next-Generation Sequencing Revealed Novel Mutations in Chinese Ataxia Telangiectasia Patients: A Precision Medicine Perspective. PLoS One. 2015. 10 (10):e0139738. [Medline].
Al-Muhsen SZ. Delayed presentation of severe combined immunodeficiency due to prolonged maternal T cell engraftment. Ann Saudi Med. 2010 May-Jun. 30(3):239-42. [Medline].
Harp J, Coggshall K, Ruben BS, Ramírez-Valle F, He SY, Berger TG. Cutaneous granulomas in the setting of primary immunodeficiency: a report of four cases and review of the literature. Int J Dermatol. 2015 Jun. 54 (6):617-25. [Medline].
Privette ED, Ram G, Treat JR, Yan AC, Heimall JR. Healing of granulomatous skin changes in ataxia-telangiectasia after treatment with intravenous immunoglobulin and topical mometasone 0.1% ointment. Pediatr Dermatol. 2014 Nov-Dec. 31 (6):703-7. [Medline].
Pachlopnik Schmid J, Güngör T, Seger R. Modern management of primary T-cell immunodeficiencies. Pediatr Allergy Immunol. 2014 Jun. 25 (4):300-13. [Medline].
Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, Fischer A. Gene therapy for severe combined immunodeficiency. Annu Rev Med. 2005. 56:585-602. [Medline].
Chinen J, Puck JM. Perspectives of gene therapy for primary immunodeficiencies. Curr Opin Allergy Clin Immunol. 2004 Dec. 4(6):523-7. [Medline].
Dupre L, Marangoni F, Scaramuzza S, Trifari S, Hernández RJ, Aiuti A. Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. Hum Gene Ther. 2006 Mar. 17(3):303-13. [Medline].
Norton RS, Pennington MW, Wulff H. Potassium channel blockade by the sea anemone toxin ShK for the treatment of multiple sclerosis and other autoimmune diseases. Curr Med Chem. 2004 Dec. 11(23):3041-52. [Medline].
Lee E, Sinha AA. T cell targeted immunotherapy for autoimmune disease. Autoimmunity. 2005 Dec. 38(8):577-96. [Medline].
Trenado A, Fisson S, Braunberger E, et al. Ex vivo selection of recipient-type alloantigen-specific CD4(+)CD25(+) immunoregulatory T cells for the control of graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2004 Jan 15. 77(1 Suppl):S32-4. [Medline].
Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005 May. 11(5):321-34. [Medline].
Bacigalupo A. Antithymocyte globulin for prevention of graft-versus-host disease. Curr Opin Hematol. 2005 Nov. 12(6):457-62. [Medline].
Hooper JA. Intravenous Immunoglobulins: Evolution of Commercial IVIG Preparations. Immunol Allergy Clin North Am. 2008 Nov. 28(4):765-78. [Medline].
Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook 2008-2009. 16th edition. Cleveland, OH: Lexi-Comp Inc; 2008.
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005 Aug 15. 62(16 Suppl 3):S5-11. [Medline].
Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacother. 2005. 25(11 Pt 2):78S-84S.
Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May. 135(2):236-46. [Medline].
Passeri E, Frigerio M, Valaperta R, Costa E, Ambrosi B, Corbetta S. Adult onset hypoparathyroidism in a patient with psychiatric illness: a 71 years delayed diagnosis of DiGeorge syndrome. J Endocrinol Invest. 2010 Dec. 33(11):852-3. [Medline].
Yoshimitsu M, White Y, Arima N. Prevention of human T-cell lymphotropic virus type 1 infection and adult T-cell leukemia/lymphoma. Recent Results Cancer Res. 2014. 193:211-25. [Medline].
Kutukculer N, Gulez N. The outcome of patients with unclassified hypogammaglobulinemia in early childhood. Pediatr Allergy Immunol. 2009 Jan 31. [Medline].
Callens C, Baleydier F, Lengline E, Ben Abdelali R, Petit A, Villarese P, et al. Clinical Impact of NOTCH1 and/or FBXW7 Mutations, FLASH Deletion, and TCR Status in Pediatric T-Cell Lymphoblastic Lymphoma. J Clin Oncol. 2012 Apr 30. [Medline].
Ally MS, Pawade J, Tanaka M, Morris S, Mitchell T, Child F, et al. Solitary mycosis fungoides: A distinct clinicopathologic entity with a good prognosis: A series of 15 cases and literature review. J Am Acad Dermatol. 2012 Apr 23. [Medline].
Bakar O, Sahin S, Cetinözman F, Willemze R, Tezcanli E, Cetin ED. Tumor-stage mycosis fungoides of the vulva successfully treated with local low-dose radiotherapy. Dermatol Ther. 2014 Oct 14. [Medline].
Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001 Jan. 27(1):20-1. [Medline].
Bennett CL, Yoshioka R, Kiyosawa H, et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3. Am J Hum Genet. 2000 Feb. 66(2):461-8. [Medline].
[Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May. 94(5 Suppl 1):S1-63. [Medline].
Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001 Jan. 27(1):68-73. [Medline].
Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol. 2005 Nov. 116(5):949-59; quiz 960. [Medline].
Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000 Dec. 106(12):R75-81. [Medline].
Driscoll DA, Sullivan KE. DiGeorge syndrome: a chromosome 22q11.2 deletion syndrome. Ochs HD, Smith CI, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999. 198-208.
Ferguson PJ, Blanton SH, Saulsbury FT, et al. Manifestations and linkage analysis in X-linked autoimmunity- immunodeficiency syndrome. Am J Med Genet. 2000 Feb 28. 90(5):390-7. [Medline].
Lavin MF, Shiloh Y. Ataxia-telangiectasia. Ochs HD, Smith CI, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999. 306-23.
Puck JM, Straus SE, Le Deist F. Inherited disorders with autoimmunity and defective lymphocyte regulation. Ochs HD, Smith CI, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999. 339-52.
Regueiro JR, Pacheco A, Alvarez-Zapata D. CD3 deficiencies. Ochs HD, Smith CI, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999. 189-97.
Sanal O, Ersoy F, Yel L, et al. Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia. J Clin Immunol. 1999 Sep. 19(5):326-34. [Medline].
Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am. 2000 Dec. 47(6):1355-69. [Medline].
Thampakkul S, Ballow M. Replacement intravenous immune serum globulin therapy in patients with antibody immune deficiency. Immunol Aller Clin North Am. 2001. 21(1):165. [Full Text].
Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001 Jan. 27(1):18-20. [Medline].
|Brand(Manufacturer)||Manufacturing Process||pH||Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)||Parenteral Form and Final Concentrations||IgA Content mcg/mL|
|Kistler-Nitschmann fractionation; pH 4 nanofiltration||6.4-6.8||6% solution: 10% sucrose, < 20 mg NaCl/g protein||Lyophilized powder 3%, 6%, 9%, 12%||720|
|Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization||5.1-6||Sucrose free, contains 5% D-sorbitol||Liquid 5%||< 50|
|Gammagard Liquid 10%
|Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation||4.6-5.1||0.25M glycine||Ready-for-use liquid 10%||37|
|Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation||4-4.5||Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycine||Liquid 10%||46|
|Cohn-Oncley fraction II/III; ultrafiltration; pasteurization||6.4-7.2||5% solution: 5% glucose, 0.3% NaCl||Lyophilized powder 5%||< 10|
(Baxter Bioscience for the American Red Cross)
|Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated||6.4-7.2||5% solution: 0.3% albumin, 2.25% glycine, 2% glucose||Lyophilized powder 5%, 10%||< 1.6 (5% solution)|
9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events
|Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization||5.1-6||10% maltose||Liquid 5%||200|
(Swiss Red Cross for the American Red Cross)
|Kistler-Nitschmann fractionation; pH 4 incubation; trace pepsin; nanofiltration||6.6||Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl||Lyophilized powder 3%, 6%, 9%, 12%||720|
|Privigen Liquid 10%
|Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration||4.6-5||L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)||Ready-for use liquid 10%||< 25|