Lymphocyte Immunization Therapy (LIT) is a therapeutic option for couples with idiopathic recurrent miscarriages and unexplained infertility. It is an immunotherapy treatment aimed at improving pregnancy outcomes in women with recurrent pregnancy loss or repeated implantation failure.

LIT works by introducing paternal antigens into a prospective mother to reduce the chances that her immune system will reject an embryo/fetus.

Under normal circumstances, the immune system should allow for a fetus to grow even though half the proteins of the fetus are different from the mother's since they are of paternal origin. However, in some cases, it is possible the maternal immune system fails to recognize that the fetus is not harmful and therefore it may "attack" the embryo.

A prior introduction of paternal factors through LIT could induce active immunological tolerance from the maternal immune system to “acclimate” the maternal immune system to the paternal proteins of the embryo.

More specifically, the proposed LIT mechanisms of action includes a humoral response with the production of anti-idiotype and asymmetric-blocking antibodies preventing maternal rejection of the fetus. This involves stimulating the maternal immune system to produce antibodies such as Anti-paternal cytotoxic antibody (APCA), Ab2, anti-T cell receptor (TCR) idiotypic antibodies, MLR-Bf, and progesterone-induced blocking factor (PIBF). These antibodies help prevent the maternal immune system, particularly T and NK cells, from recognizing paternal HLA antigens by blocking these antigens. Additionally, LIT is reported to reduce NK cell activity, downregulate the expression of maternal IL-2 receptors, shift the immune response toward Th1, improve the Th1/Th2 balance, and increase Treg responses over Th17 responses.

LIT was originally recommended by Dr Alan E. Beer, a pioneer in the field of reproductive immunology and although it has been shown to increase in live birth rates and decreased miscarriage rates in numerous uncontrolled studies and case reports, it is nevertheless still considered experimental and is not FDA or otherwise approved as an official treatment and that there is no randomized controlled data to support its efficacy.

For this reason, unfortunately, LIT is not universally available and its use varies by country and region, often making it less accessible for patients worldwide that might need it.

Current systematic review data suggests up to a 45% increase in live-birth rate.

Efficacy data overall supports the utility of LIT although controversy does exist. There are numerous studies that support positive impact, increase in live birth rates and decreased miscarriage rates, although no well-done randomized controlled trial(s) exist to prove that this therapy is beneficial in cases recurrent implantation failure and/or recurrent pregnancy loss beyond any doubt.

The most recent systematic review and meta-analysis from the American Journal of Reproductive Immunology demonstrates that there is a 45% increase in live birth for patients doing LIT compared to those who received placebo or no treatment (RR= 1.97,95% CI= 1.53-2.53).

In addition the results of the analysis showed:

• A trend towards benefit with paternal LIT

• Multiple doses of immunotherapy before pregnancy and low dose LIT showed significant benefit.

Studies have also shown varying degrees of effectiveness based on individual immune profiles and underlying causes of infertility or pregnancy loss.

The treatment is usually administered in multiple sessions. The exact number of sessions and timing depends on the individual case and protocol recommended by the reproductive immunologist. Although usually individually tailored to meet the specific needs of each patient, a typical LIT Immunotherapy protocol is performed by intradermal injections of isolated mononuclear cells with 15 to 30 day intervals in one or more “priming” or “maintenance” sessions followed by one or more “booster” sessions at specific points during pregnancy. Usually these include:

1) Confirmation of pregnancy (on a positive doubling hCG test)

2) Detection of fetal heartbeat (6-8 weeks)

3) Nuchal Translucency scan (11-14 weeks)

Less or more LIT sessions may be required based on patient clinical history and primary and pregnancy monitoring lab test results.

Pregnancy monitoring testing of LAD, NK cells, Regulatory T-Cells (Tregs), NK cell cytotoxicity and Th1/Th2 cytokine ratio is advisable to evaluate therapeutic efficacy of LIT and to adjust number and frequency of LIT sessions.

The initial results of the treatment should be generally visible at 4-12 weeks. Additional sessions can be necessary for full effect. Fertility therapy or natural attempts at conception should be considered within the 1–3-month time frame following treatment. Of course, all individuals are different so there will be variations from one person to the next.

There are no significant concerns regarding LIT safety, although there can be pain, infection and temporary or permanent scarring at the injection site. Because the injections occur at the forearm, scarring that is permanent can be cosmetically displeasing. Additional reactions including hypersensitivity and/or anaphylaxis have been reported, although such cases are extremely rare.

A list of risks, complications & side effects includes:

1) Pain at the injection site

2) Bleeding, Bruising and/or Infection as with any type of injection

3)Short lasting pinkness/redness (flushing) of the skin

4) An allergic reaction to the solution

5) Injury to a nerve and/or muscle

6) Itching at the injection site(s)

7) Nausea /vomiting

8) Dizziness or fainting

9) Temporary blood sugar increase

10) Swelling

Finally, a 2006 German follow-up study by Kling et al. covering a high number of women in a period of seven years, reported that there were no cases of anaphylaxis, autoimmune, or graft versus host diseases or any other significant side-effect that could be linked to LIT treatment.

Patients with the following conditions are NOT CANDIDATES for LIT:

1) Acute: and Chronic Infections

2) Skin diseases (i.e. SLE, porphyria, allergies) 3) Cancer

4) Chemotherapy treatments

5) Severe: metabolic and systemic disorders

6) Abnormal platelet function (blood disorders, i.e. Hemodynamic instability, Hypofibrinogenemia, Critical Thrombocytopenia)

7) Chronic Liver Pathology

8) Anti-coagulation therapy

9) Underlying Sepsis

10) Systemic use of corticosteroids within two weeks of the procedure.